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CN102088935A - Permeant delivery system and methods for use thereof - Google Patents

Permeant delivery system and methods for use thereof Download PDF

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Publication number
CN102088935A
CN102088935A CN2009801200553A CN200980120055A CN102088935A CN 102088935 A CN102088935 A CN 102088935A CN 2009801200553 A CN2009801200553 A CN 2009801200553A CN 200980120055 A CN200980120055 A CN 200980120055A CN 102088935 A CN102088935 A CN 102088935A
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China
Prior art keywords
permeable membrane
paster
administration phase
hours
membrane thing
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Granted
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CN2009801200553A
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CN102088935B (en
Inventor
弗兰克·泰格里弗瑞
艾伦·史密斯
戴维·艾斯考瑞
高拉夫·托拉
麦瑞克·宝迪斯
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Passport Technology Co
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Altea Therapeutics Corp
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Priority to CN201510333806.7A priority Critical patent/CN105126241B/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Anesthesiology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Emergency Medicine (AREA)
  • Medical Informatics (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Media Introduction/Drainage Providing Device (AREA)

Abstract

Disclosed are a patch, system, and method for delivery of a permeant composition into a subject via at least one formed pathway through a biological membrane of the subject. The patch comprises a matrix, at least one hydrophilic permeant disposed within the matrix, wherein at least a portion of the permeant can dissolve in biological moisture received from the subject, and at least one permeability enhancer disposed within the matrix. Also disclosed are systems and methods for delivery of a permeant composition into a subject via at least one formed pathway through a skin layer of the subject.

Description

Permeable membrane thing delivery system and using method thereof
Prioity claim
The application requires to be filed in the priority of No. the 61/040th, 744, the U.S. Provisional Patent Application series on March 31st, 2008, and it incorporates its content into this paper in full by reference.The application also requires to be filed in the priority of No. the 61/133rd, 101, the U.S. Provisional Patent Application series on June 25th, 2008, and it incorporates its content into this paper in full by reference.
Invention field
The present invention relates generally to percutaneous permeable membrane thing and send the field, and more specifically, relate to the device, the system and method that use percutaneous permeable membrane thing to send.
Background of invention
Gone on the market and have been used for multiple treatment indication in over 20 years of past, transdermal drug delivery system.Usually, transdermal delivery system is made into the multiple layer polymer thin layer, and wherein drug depot or pharmaceutical polymer substrate are clipped between two polymeric layers: produce enclosed environment and prevent the outside impermeability backing layer of the drug loss by the backing surface and as the inner polymeric layer of binder film and/or rate controlling membranes performance function.When designing for the drug depot drug depot, storage storehouse, described storage storehouse is clipped between backing and the rate controlling membranes.Medicine only through-rate controlling diaphragm discharges, described rate controlling membranes can be micropore or atresia.In drug depot was separated, medicine can be the form of solution, suspension or gel or be scattered in the solid polymer substrate.On the outer surface of polymeric film, can use the thin layer of a medicine adhesive polymer compatible, hypoallergenic property.
For the drug matrices design, there are two types, promptly medicine is arranged in the system and the substrate disperse system of binding agent (drug-in-adhesive).Be arranged in the system of binding agent at medicine, drug depot is by following formation: medicine is scattered in the binder polymer, and then the polymer adhesive of pastille is layered on the impermeability backing layer by solvent cast or by the described binding agent of fusing (for hot-melt adhesive).The not adhesive polymer layer of pastille is used at top in the storage storehouse.For the substrate disperse system, be evenly dispersed in medicine hydrophilic or the lipophilic polymeric matrix in and be fixed in by solvent cast or extruding on the backing layer of medicine impermeable.Applied adhesives forms the periphery binding agent, rather than binding agent is applied on the face of drug depot.
Most conventional contain lipophilic in nature small-molecule drug (＜500 dalton) through skin product, this allows its solubilized in the lipid bilayer of skin outer layer and the lipid bilayer diffusion by skin outer layer, the lipid bilayer of described skin outer layer is a horny layer.Most ofly contain the medicine of lipophilic base form through skin product, but not hydrophilic form or water soluble salt form.Dermal delivery is limited to micromolecule usually, enters in the body by the paster zone of fair-sized to allow enough flux.For increasing the percutaneous flux, the chemosmosis reinforcing agent is added percutaneous preparation.But, use the chemosmosis reinforcing agent successfully not realize hydrophilic drugs or water soluble drug or any flux that is enough to reach treatment level greater than 1000 daltonian molecules.Thereby, need in the art to be used to realize give individual improved mthods, systems and devices with treatment delivery rate dermal delivery with the permeable membrane thing.
The invention summary
The invention provides and be used for device, system and method that the permeable membrane thing is sent by the biomembrane of individuality.
In first aspect, the present invention comprises substrate, at least a hydrophilic permeable membrane thing and at least a paster that is positioned over the permeability reinforcing agent in the described substrate, and wherein the described hydrophilic permeable membrane thing to small part can be dissolved in from the biological moisture that individuality obtains.
In one embodiment of the invention, described hydrophilic permeable membrane thing is a bioactivator.In specific embodiments, described hydrophilic permeable membrane thing is an albumen.In another embodiment, described hydrophilic permeable membrane thing is a micromolecule.In one embodiment, described hydrophilic permeable membrane thing is selected from Exenatide (exenatide), citric acid fentanyl, hydromorphone or insulin.
In another embodiment of the present invention, described permeability reinforcing agent is the pH controlling agent.In specific embodiments, described permeability reinforcing agent is selected from disodium citrate, succinic acid or Tris (tris).
In still another embodiment of the present invention, described substrate is polymeric matrix.In one embodiment, described polymeric matrix comprises single polymers.In specific embodiments, described polymer is selected from insoluble polymer or water-soluble polymer.Ethane-acetic acid ethyenyl ester and ethyl cellulose are typical insoluble polymers.Polyvinyl alcohol is a typical water soluble polymers.
In still other embodiments of the present invention, described polymeric matrix comprises two or more polymer.In one embodiment, described two or more polymer are selected from insoluble polymer, water-soluble polymer or its combination.In specific embodiments, described polymeric matrix comprises ethane-acetic acid ethyenyl ester and ethyl cellulose.In another embodiment, described polymeric matrix comprises ethane-acetic acid ethyenyl ester and polyvinyl alcohol.
In another embodiment of the present invention, described hydrophilic permeable membrane thing is continued scope, and extremely about 7 days administration phase was delivered to individuality from about 5 minutes.In one embodiment, lasting about 7 days administration phase of described hydrophilic permeable membrane thing is delivered to individuality.In another embodiment, lasting about 3 days administration phase of described hydrophilic permeable membrane thing is delivered to individuality.In other embodiments, extremely about 36 hours administration phase was delivered to individuality from about 12 hours described hydrophilic permeable membrane thing to be continued scope.In another embodiment still, described hydrophilic permeable membrane thing is continued about 24 hours administration phase be delivered to individuality.
In other embodiments of the present invention, described paster also comprises the dissolubility controlling agent.In one embodiment, described dissolubility controlling agent is a salt.In specific embodiments, described dissolubility controlling agent is selected from sodium chloride or ammonium sulfate.
In specific embodiments, the present invention is used for paster that Exenatide is sent by the biomembrane of individuality, wherein said paster comprises polymeric matrix and at least a permeability reinforcing agent that contains Exenatide, and wherein the described Exenatide to small part is dissolved in from the biological moisture that described individuality obtains.In specific embodiments, described permeability reinforcing agent is the pH controlling agent.In one embodiment, described dissolubility controlling agent is a succinic acid.In other specific embodiments, described polymeric matrix comprises ethane-acetic acid ethyenyl ester and ethyl cellulose.In specific embodiments, Exenatide is continued about 5 hours, and extremely about 7 days administration phase is delivered to described individuality.In one embodiment, lasting about 24 hours, about 3 days of Exenatide or about 7 days administration phase are delivered to individuality.
In other specific embodiments, the present invention is used for paster that insulin is sent by the biomembrane of individuality, wherein said paster comprises polymeric matrix and at least a permeability reinforcing agent that contains insulin, and wherein the insulin to small part is dissolved in from the biological moisture that described individuality obtains.In specific embodiments, described permeability reinforcing agent is the pH controlling agent.In specific embodiments, described pH controlling agent is a Tris.In another embodiment, described polymeric matrix comprises ethane-acetic acid ethyenyl ester and polyvinyl alcohol.In specific embodiments, insulin is continued about 5 hours, and extremely about 7 days administration phase is delivered to individuality.In one embodiment, lasting about 24 hours, about 3 days of insulin or about 7 days administration phase are delivered to individuality.
According to second aspect, the present invention is the paster that comprises Exenatide and at least a permeability reinforcing agent.Described permeability reinforcing agent can be about first aspect present invention any permeability reinforcing agent mentioned above.In specific embodiments, described permeability reinforcing agent is the pH controlling agent.In one embodiment, described paster comprises polymeric matrix, and wherein said polymer can be any polymer mentioned above about first aspect present invention.In another embodiment, described paster comprises permeable membrane thing storage storehouse.In another embodiment still, described paster also comprises the dissolubility controlling agent, and wherein said dissolubility controlling agent can be any dissolubility controlling agent mentioned above about first aspect present invention.In other embodiments still, Exenatide phase that continues medication is delivered to individuality, the wherein said administration phase can be any time mentioned above about first aspect present invention.
According to the third aspect, the present invention comprises at least a permeable membrane thing and at least a paster that is selected from the pH controlling agent of succinic acid or Tris.Described permeable membrane thing can be any permeable membrane thing mentioned above about first aspect present invention.In another embodiment, described paster comprises polymeric matrix, and wherein said polymer can be any polymer mentioned above about this paper first aspect.In other embodiments still, described paster comprises permeable membrane thing storage storehouse.In other embodiments still, described permeable membrane thing phase that continues medication is delivered to individuality, the wherein said administration phase can be any time mentioned above about first aspect present invention.
In a specific embodiments, the present invention comprises the storage of permeable membrane thing storehouse, Exenatide and at least a paster that is selected from the pH controlling agent of succinic acid or Tris.
In another embodiment, the present invention comprises permeable membrane thing storage storehouse, insulin and is selected from succinic acid or the paster of the pH controlling agent of Tris.
According to fourth aspect, the present invention is used for system that the permeable membrane thing is sent by the biomembrane of individuality, described system comprises perforator and paster, wherein said paster comprises substrate and at least a hydrophilic permeable membrane thing and is positioned at least a permeability reinforcing agent in the described substrate, wherein can be dissolved in the biological moisture that described individuality provides by one or more micropores that formed by described perforator to the described hydrophilic permeable membrane thing of small part.
In one embodiment, described perforator is the hot piercing device.In another embodiment, described perforator is selected from machine drilling device, laser beam perforation device or hydraulic perforating gun.
Various embodiments mentioned above about first aspect present invention also are applicable to a fourth aspect of the present invention, comprise hydrophilic permeable membrane thing, permeability reinforcing agent, comprise the substrate of different polymers compositionss, other dissolubility controlling agent and administration phase.
In specific embodiments, the present invention is used for system that Exenatide is sent by the biomembrane of individuality, it comprises perforator and paster, wherein said paster comprises polymeric matrix and at least a permeability reinforcing agent that contains Exenatide, wherein is dissolved in the biological moisture that described individuality provides and lasting scope is delivered to described individuality from about 5 minutes to 7 days administration phase to the Exenatide of small part.In specific embodiments, described perforator is the hot piercing device.In another embodiment, described permeability reinforcing agent is the pH controlling agent.In one embodiment, described pH controlling agent is a succinic acid.In another embodiment, described polymeric matrix comprises ethane-acetic acid ethyenyl ester and ethyl cellulose.In another embodiment, Exenatide is continued be selected from about 24 hours, about 3 days or about 7 days administration phase be delivered to individuality.
In another embodiment, the present invention is used for system that insulin is sent by the biomembrane of individuality, it comprises perforator and paster, wherein said paster comprises polymeric matrix and at least a permeability reinforcing agent that contains insulin, wherein is dissolved in the biological moisture that described individuality provides to the insulin of small part.In specific embodiments, described perforator is the hot piercing device.In another embodiment, described permeability reinforcing agent is the pH controlling agent.In one embodiment, described pH controlling agent is a Tris.In another embodiment, described polymeric matrix comprises ethane-acetic acid ethyenyl ester and polyvinyl alcohol.In another embodiment, insulin is continued be selected from about 24 hours, about 3 days or about 7 days administration phase be delivered to individuality.
According to the 5th aspect, the present invention is used for system that Exenatide is sent by the biomembrane of individuality, and described system comprises perforator and paster, and wherein said paster comprises Exenatide and at least a permeability reinforcing agent.Described perforator can be any perforator mentioned above about fourth aspect present invention.In specific embodiments, described perforator is the hot piercing device.Be selected from machine drilling device, laser beam perforation device or hydraulic perforating gun.
Various embodiments mentioned above about second aspect present invention also are applicable to a fifth aspect of the present invention, comprise the permeability reinforcing agent, comprise the substrate of different polymers compositionss, other dissolubility controlling agent and administration phase.In one embodiment, described paster comprises permeable membrane thing storage storehouse.
According to the 6th aspect, the present invention is used for system that Exenatide is sent by the biomembrane of individuality, described system comprises perforator and paster, and wherein said paster comprises at least a permeable membrane thing and at least a pH controlling agent that is selected from succinic acid or Tris.
Various embodiments mentioned above about third aspect present invention also are applicable to a sixth aspect of the present invention, comprise the permeability reinforcing agent, comprise the substrate of different polymers compositionss, other dissolubility controlling agent and administration phase.In one embodiment, described paster comprises permeable membrane thing storage storehouse.
According to the 7th aspect, the present invention is used for method that the permeable membrane thing is sent by the biomembrane of individuality, described method is included in to form one or more micropores in the described biomembrane and paster and described one or more micropores are carried out physics and contacts to allow the step of sending of described permeable membrane thing, wherein said paster comprises polymeric matrix and at least a hydrophilic permeable membrane thing and at least a permeability reinforcing agent that is positioned in the described substrate, wherein can be dissolved in the biological moisture that described individuality provides by one or more micropores that formed by described perforator to the described hydrophilic permeable membrane thing of small part.
In one embodiment, described one or more micropore is formed by the hot piercing device.In another embodiment, described one or more micropore is to be formed by the device that is selected from mechanical sting device, ablative device or hydraulic pressure device.In specific embodiments, described micropore is formed by heat-conduction component, and the physics that described heat-conduction component and biomembrane carry out essence contacts transmitting enough energy to described biomembrane, thus the described biomembrane of heating ablation.
Various embodiments mentioned above about the present invention first, second and the third aspect also are applicable to a seventh aspect of the present invention, comprise permeable membrane thing, permeability reinforcing agent, comprise substrate, the permeable membrane thing storage storehouse of different polymers compositionss, other dissolubility controlling agent and administration phase.
Others of the present invention will partly be set forth in detailed description, accompanying drawing and any claim subsequently, and partly be derived from detailed description, maybe can know by practice of the present invention.Be to be understood that above concise and to the point description and detailed description hereinafter all only are exemplary with illustrative, and are not to be to limit the invention according to disclosed.
The accompanying drawing summary
The accompanying drawing of incorporating this description into and constituting the part of this description illustrates some aspect of the present invention, and is used from description one and explains principle of the present invention, and and unrestricted.
Fig. 1 has showed the side view of the permeable membrane thing delivery patch of root a tree name one aspect of the present invention.
Fig. 2 has showed the side view of permeable membrane thing delivery patch according to an aspect of the present invention, and the surface area of the increase that is provided by eyelet is provided wherein said delivery patch.
Fig. 3 has showed the side view that permeable membrane thing is according to an aspect of the present invention sent, and that stores wherein that storehouse or substrate comprises that a plurality of stacked arrangement arrange sends storage storehouse or substrate.
Fig. 4 has showed exemplary percutaneous permeable membrane thing delivery patch according to an aspect of the present invention.
Fig. 5 has showed the sketch map of electro-osmotic pumps assembling according to an aspect of the present invention.
Fig. 6 has showed exemplary percutaneous permeable membrane thing delivery patch according to an aspect of the present invention, and wherein said paster assembling also comprises first, second and third electrode assembling.
Fig. 7 sends the dynamic (dynamical) chart of exemplary release in vitro in storage storehouse for report permeable membrane thing of the present invention.
Fig. 8 is the chart of the illustrative drug kinetics spectrum data of having reported that permeable membrane thing is according to an aspect of the present invention sent storage storehouse or substrate.
Fig. 9 has reported for permeable membrane thing according to the present invention and has sent the storage storehouse that the variation that polymer and citric acid fentanyl load is not to there being the influence of serum drug level in the hair rat.
Figure 10 has reported after using placebo or comprising the film of medicine not have fentanyl serum-concentration in the hair rat.
Figure 11 adds the chart contain as the effect of the insulin preparation of the Tris of permeability reinforcing agent for having illustrated with water-soluble polymer polyvinyl alcohol (PVA).
Figure 12 adds the chart contain as the effect of the insulin preparation of the Tris of permeability reinforcing agent for having illustrated with insoluble polymer ethyl cellulose (EC).
Figure 13 has illustrated that various permeability reinforcing agents are for the chart that does not have the influence that Exenatide is sent in the hair rat.
Figure 14 has illustrated in the preparation that design is sent in order to the prolongation that realizes the Exenatide above 24 hours the chart of the effect of succinic acid (SA) and ethyl cellulose (EC).
Figure 15 has showed the effect that ethyl cellulose control Exenatide discharges from succinic acid and disodium citrate film.
Figure 16 has illustrated that the permeability enhancer component is for the chart of Exenatide from the influence of the release in vitro of the Exenatide film that comprises ethane-acetic acid ethyenyl ester and purpose permeability reinforcing agent.
Figure 17 has showed the influence of permeability reinforcing agent concordance for the maintenance of hole permeability.
Detailed Description Of The Invention
By before reference the following detailed description, embodiment and claim and they and description afterwards, can more easily understand the present invention.
Before open and this composition of description, device, system and/or method, be to be understood that, unless otherwise provide, the invention is not restricted to disclosed special article, device, system and/or method. Should also be appreciated that term used herein is not the intention restriction for the purpose of describing concrete aspect only.
Provide following description of the invention as in the best of the present invention, at present known embodiment, realizing instruction of the present invention. Various equivalent modifications should be recognized, can carry out multiple change to described embodiment, and still can obtain useful result of the present invention. It is evident that equally some required benefit of the present invention can not use by selecting some feature of the present invention further feature to obtain. Thereby those skilled in the art should recognize, all be feasible to multiple change of the present invention and variation, even be desirable in some cases, and be a part of the present invention to multiple change of the present invention and variation. Therefore, providing following describes as to the example explanation of the principle of the invention but not limit it.
Singulative " a ", " an " and " the " comprise that plural number refers to thing as used herein, specify unless have in addition in the context clearly. Therefore, for example, for the paster that comprises " bioactivator ", it comprises the aspect with two or more bioactivators, specifies unless have in addition in the context clearly.
Scope can be expressed as from " pact " particular value and/or to " pact " another particular value in this article. When explaining such scope, comprise on the other hand from a described particular value and/or to described another particular value. Similarly, by using antecedent " approximately (approximately) " or " approximately (about) " that numeric representation during as approximation, is to be understood that this particular value consists of on the other hand. Should also be appreciated that, the end value of each scope, relevant with another end value and with the irrelevant situation of another end value under, all be significant.
Event or the situation described subsequently of term " optional " or " randomly " expression can take place or can not take place as used herein, and this description has comprised the situation when this event or situation take place and the situation when not taking place.
As used herein " percentage by weight (the weight percent) " of component or " percentage by weight (percent by weight) " unless specialize reverse situation, is based on the preparation that comprises described component or the gross weight of composition.
Term or phrase " effectively ", " effective dose " or " right ... effective condition " refer to bring into play amount or the condition of function or character as used herein, for described function or character expression effective dose. Just as will be noted, required exact amount or specified conditions will be different with embodiment, and it depends on generally acknowledged variable factor, for example employed material and the treatment conditions of observing. Therefore, stipulate that definite " effective dose " or " right ... effective condition " is always unfeasible. But, be to be understood that those skilled in the art only utilize normal experiment can easily determine suitable effective dose or condition for validity.
" therapeutic dose " of permeable membrane thing or " treatment effective dose " refers to provide the amount of the permeable membrane thing of results needed as used herein. Described results needed can be the expected results of described permeable membrane thing administration, unexpected result or even uninsured consequences.
Term " paster " as used herein with limiting examples, can comprise conventional medicament storage storehouse or drug matrices paster or the paster of any other type of being adapted at using in the transdermal drug delivery technology. In an embodiment of drug depot design, described storage storehouse can be clipped between backing and the rate controlling membranes. Medicine can only discharge by described rate controlling membranes, described rate controlling membranes can be micropore or atresia. In drug depot was separated, medicine can be, such as but not limited to, the form of solution, suspension or gel or be scattered in the solid-state construction. On the outer surface of described film, drug administration binder polymer thin layer compatible, hypoallergenic property optionally. In an embodiment of drug matrices design, comprise two kinds of common known types, medicine is arranged in system and the matrix decentralized system of adhesive. Be arranged in an embodiment of the system of adhesive at medicine, described drug depot can be by following formation: medicine is scattered in the binder polymer, and then the polymer adhesive of pastille is layered on the impermeability back sheet by solvent cast or by the described adhesive of fusing (for hot-melt adhesive). The not adhesive polymer layer of pastille can be used in top in the storage storehouse. In an embodiment of matrix decentralized system, be evenly dispersed in medicine hydrophilic or the lipophilic polymer substrate in and be fixed on the back sheet of medicine impermeable. In another embodiment, applied adhesives forms the periphery adhesive, rather than adhesive is applied on the face of drug depot. The paster that can be positioned over the form of ownership on the skin that comprises the paster of above-mentioned conventional medicament storage storehouse or drug matrices form is included as embodiment of the present invention.
Term " hydrophily permeable membrane thing " refers to have the permeable membrane thing for the affinity of moisture as used herein. On the one hand, described moisture may reside in subcutaneous fluid or is provided by subcutaneous fluid. Described subcutaneous fluid can be in the cell and/or extracellular liquid. On the one hand, hydrophily permeable membrane thing can be substantially water miscible at least, so as described hydrophily permeable membrane thing in case with water or for example the moisture source of subcutaneous fluid contact, described hydrophily permeable membrane thing is dissolved in the described subcutaneous fluid at least basically. On the other hand, described hydrophily permeable membrane thing can be insoluble in the described subcutaneous fluid substantially, but can form the suspension of corpuscular property hydrophily permeable membrane thing in described subcutaneous fluid. The hydrophily permeable membrane compositions that also uses such as this paper can comprise one or more hydrophily permeable membrane things as indicated above.
" subcutaneous fluid " or " biological moisture " can include but not limited to moisture, blood plasma, blood, one or more protein, interstitial fluid, Skin tissue fluid, the liquid from any skin layer, sweat, serum, lymph liquid and/or above-mentioned two or more any combination as used herein. On the one hand, be the moisture source that comprises water according to subcutaneous fluid of the present invention.
Term " abiotic degradable " refers to material, compound or composition as used herein, when it contacts with subcutaneous fluid, does not substantially degrade, does not dissolve or be not etched. On the one hand, abiotic degradable material, compound or composition can be substantially water-fast material, compound or composition.
Term " permeable membrane thing availability " refers in the administration phase, be positioned over the percentage from the paster dermal delivery to individuality in the initial permeable membrane thing content in the permeable membrane thing delivery patch at predetermined permeable membrane thing as used herein.
Term " individuality " refers to have at least one biomembranous any lived biology as used herein, can obtain liquid by described biomembrane. On the one hand, exemplary biomembrane can be at least a skin layer, can obtain subcutaneous fluid by described skin layer. For example, on the one hand, individuality can be plant. Selectively, on the other hand, described individuality can be animal. On the one hand, described animal can be mammal. Aspect selectable, described animal can be nonmammalian. Described animal also can be cold-blooded animal, for example fish, reptile or amphibian. Selectively, described animal can be warm-blooded animal, for example people, agricultural animal, performing animal or or even animal used as test. Therefore, be to be understood that the present invention is not limited to the purposes relevant with any specific individuality or population of individuals.
As used herein " biomembrane " be included in the cell or cell peripheral as the layer of the sealing of barrier or the layer that separates. In some aspects, described biomembrane can be by lipid molecule and once in a while, the lipid bilayer that forms of staggered albumen. Biomembrane used herein also can limit space or the separation of sealing, and wherein cell can keep being different from chemistry or the biological chemical environment of the external environment condition of described space or separation. In some aspects, described biomembrane can be selective permeable structure, wherein attempts to determine by its atom and bulk of molecule, electric charge and other chemical property whether described atom and molecule can pass through. In one aspect, described biomembrane can be mucous membrane. Exemplary mucous membrane can include but not limited to, oral film, gum film, gastrointestinal membranes, cervical membrane, vaginal membranes, rectum inner membrance, nasal cavity inner membrance, cheek film and ocular membrane. On the other hand, described biomembrane can be skin layer.
" skin layer " can be individual any one or a plurality of epidermal area as used herein. For example, on the one hand, skin layer comprises the outermost layer of skin, i.e. cuticula. Aspect selectable, skin layer can comprise subcuticular one or more layers epidermis, usually is characterized as stratum granulosum, spinous layer (malpighian layer) and basalis (germinal layer). It will be understood by those skilled in the art that by subcuticular epidermal area transhipment or absorbing the permeable membrane thing has basically minimum resistance or does not have resistance. Therefore, in one aspect of the invention, at least one passage that forms in the individual's skin layer is the passage in the individual cuticula.
" reinforcing agent ", " chemical intensifier ", " penetration enhancer ", " penetration enhancers ", " permeability reinforcing agent " etc. comprise that all increase permeable membrane thing, analyte or other molecule are by the reinforcing agent of biomembrane or the flux in organizing liquid as used herein. Intention comprises that all upset compound and solvent and any other chemical intensifier of cell envelope. In addition, intention comprises pH controlling agent, solubility control agent (comprising ionic strength controlling agent, salting-out agents and water-soluble polymer) and filler. In addition, comprise all active force enhancing technology, include but not limited to, local deformation, phonophoresis, iontophoresis or the electroporation of application of sonic energy, machinery suction, pressurization or tissue. In some cases, described hydrophily permeable membrane thing also simultaneously (with its effect as the permeable membrane thing) or separately as the permeability reinforcing agent. One or more enhancing technology can be united or simultaneously associating successively. For example, can at first use chemical intensifier so that capillary wall is permeable, and can use then iontophoresis field or acoustic energy field and enter and surround and comprise in those tissues of capillary bed to drive energetically the permeable membrane thing.
" through (transdermal) of skin " or " through (percutaneous) of skin " comprises that the permeable membrane thing enters and by the passing through of one or more skin layers as used herein, thereby reaches effective treatment blood level or the local organization level of permeable membrane thing.
" opening of formation ", " artificial opening " or " micropore " expression are suitable for sending or passing through biomembranous any physics breach of the size of its extracting liq as used herein. Therefore, " opening of formation ", " artificial opening " or " micropore " refer to produce to the biomembrane desired depth or by biomembranous hole, opening or breach. In one embodiment, the term micropore instructs and to cause biofluid and produce to the result of any skin grinding technique of skin surface. In one embodiment, described opening can pass through such as United States Patent (USP) the 5th, 885, No. 211 and the 7th, 141, the thermal energy conduction described in No. 034 forms, incorporate its instruction into this paper by reference, perhaps by machining, by pyrotechnic or by forming with RF ablation. In some aspects, the size in hole or hole can be for example diameter 1-1000,5-700,10-500,50-300,100-250,50-100 or 70-90 micron. Described hole or hole can be any shapes, such as cylinder, crack, hole, square, ditch shape, volcano degree of lip-rounding etc. Be to be understood that for easy term micropore uses with singulative, but described device, system and method can form the array in a plurality of openings or hole.
As used herein, " perforation ", " micropunch " or any such similar terms are illustrated in tissue or the biomembrane or the formation by tissue or biomembrane duck eye or breach (being also referred to as subsequently " micropore "), thereby weaken this biomembranous barrier, be used in order to select at least a permeable membrane thing of allowing of purpose pass through to opposite side from this biomembranous side, described tissue or biomembrane be skin or mucous membrane or biological skin for example. Preferably, the hole that forms like this or " micropore " diameter are about the 1-1000 micron and extend into fully biomembrane destroying cuticular barrier, and following tissue are not caused adverse effect. In other embodiments, the hole or the micro-pore diameter that form like this are about 1-1000,5-700,10-500,50-300,100-250,50-100 or 70-90 micron. Be to be understood that for easy term " micropore " uses with singulative, but device of the present invention can form a plurality of artificial openings. Perforation can reduce biomembranous barrier in the body, is used for selecting purpose or is used for some medical science or operation technique. The opening difference that micropunch process as referred to herein and electroporation form mainly is the typical minimum dimension of micropore, the typical minimum dimension bandpass of described micropore is not less than about 1 micron also common degree of depth at least about 1 micron, yet usually only has several nanometers at any yardstick with the opening that electroporation forms. However, the permeable membrane thing entered by micropore tissue than deep layer after, electroporation is useful for the permeable membrane thing that promotes biological target tissue picked-up below outer to select. Be used for the application's purpose, " perforation " and " micropunch " used convertibly.
" micropunch device " or " perforator " are the assemblies of micropunch device that can micropunch. The example of micropunch device or perforator comprises, but be not limited to: the hot piercing device, comprise and have the device that one or more filaments, heat-conduction component and optics heat local dyestuff/absorbed layer, described filament can be sent to conductibility by directly contacting with biomembrane heat energy, thereby cause the melting of some part of film, this melts enough deeply to form micropore, described heat-conduction component and biomembrane carry out the physical contact of essence, thereby enough energy are delivered to biomembrane with the described biomembrane of heating ablation; The machinery ablating device comprises the array of motor machine actuator, microknife (microlancet) and entity or hollow microneedle pin or blade; The RF ablation device, acoustic energy melts device; Laser ablation system; The hydraulic pressure sting device comprises the high-pressure spray puncture outfit; Utilize the technology of the physical abrasion of skin surface; Corium trajectory delivery apparatus etc. United States Patent (USP) the 7th, 141, the film organizational interface (Thin Film Tissue Interface) of describing in No. 034 is other examples of perforator, it incorporates it into this paper in full by reference. " micropunch device " and " perforator " use convertibly as used herein.
" film organizational interface " or " TFTI " are used to describe and utilize electric current to pass through the heat energy that resistive element produces to produce the device of micropore and manufacture method and the feature operation method of described TFTI device. The TFTI device can produce one or more micropores at multiple biomembrane. TFTI has and comprises for strengthening analyte monitoring and such as the application of the hot micropunch of application on human skin of sending of the permeable membrane thing of medicine or tattoo dye. TFTI is characterized as it can be fast and effectively produces micropore on biomembranous surface pattern or array. Described pattern can be any how much intervals with micropore of various possible hole density. In one embodiment, hole density up to per 0.2 square millimeter of hole and hole density can coverage from several square millimeters to greater than total punched areas of hundreds of square centimeters, comprise 0.005-800,0.01-500,0.1-500,1-300,10-200,25-100 and 50-75 square centimeter. The TFTI device is designed to thin, pliable and tough and consistent structure, and this structure can form the interface between biomembrane and controller. Selectively, TFTI can self integrating controller and the device of this integration can contact with biomembrane. Controller part in the TFTI each punctured element or electrode or provide the required signal of telecommunication such as other effect assemblies such as piezoelectric transducers, thereby realize perforation or other functions of TFTI, include but not limited to the impedance measurement of iontophoresis, phonophoresis, electroporation or the tissue that contacts. TFTI is pliable and tough and can be obedient to the biomembranous shape of target. TFTI is made into very thin, in light weight and can separates with paster and use or use with the form of integrating, and by umbilical cable be connected with controller or power supply to allow to be more convenient for user's configuration. When having merged one or more controlled effect additional flux Enhanced feature among the TFTI (described controlled effect additional flux Enhanced feature such as but not limited to, pressure is regulated, mechanical handling, iontophoresis, electric osmose, phonophoresis or electroporation), can pass through remote controller module, mode with the walkthrough program, with the mode of controlling by the user to the controller input or the activation of controlling this additional flux controlling feature in the automated closed-loop mode, wherein according to the mensuration level of the analyte of selecting in biological or biological in the function of other measurability matter, regulate permeable membrane thing infusion rates. Described other measurability matter can comprise heart rate, blood pressure, body temperature, breathing and skin surface electrical conductivity. For example, in one embodiment, the speed of controlling infusion of insulin according to the real-time measurement values of the interstitial fluid of biology or glucose in serum concentration is useful. In another embodiment, for some treatment compound, those compounds that particularly have narrower treatment window, described treatment window is defined as effective levels of drugs than the very intolerable situation of adverse side effect, measurable Level tune infusion rates according to this compound in biological is desirable, thereby be allowed for reaching and keeping the method for very accurate and oneself's adjustment of the drug concentration in the required treatment window, need not to consider weight in patients or metabolism. In the Design and manufacture of TFTI, form and much can be used for the performance multiple function in the conductive traces of TFTI. For example, be used for to be used to the closed loop feedback control of micropunch or to merge enhancing as the electrode for the iontophoresis that after micropore forms, carries out or electroporation process with the track that causes thermal cycle to resistance punctured element delivered current short pulse.
" iontophoresis " refers to by using two or more electrodes to apply external electrical field to tissue surface as used herein, and the ionized form medicine that the relevant water flux of ion transport (electric osmose) is carried or non-ionic drug delivery be in tissue, the perhaps similarly extraction of biofluid or analyte.
" electroporation " refers to that by the opening in the generation cell membrane of electric current, described opening number magnitude is less than micropore as used herein. The opening that forms with electroporation only has several nanometers, for example 1-10 nanometer usually on arbitrary dimension. In an example, the permeable membrane thing entered by micropore tissue than deep layer after, electroporation is for promoting that biological target tissue below outer is useful to the cellular uptake of the permeable membrane thing selected.
" phonophoresis " or " ultrasonic processing " refers to vibrate piezo-electric crystal or other electromechanical element and the acoustic energy that produces as used herein, described vibration is to be communicated with electric current and to cross described material and take place by making, and described acoustic energy can comprise and usually is described as hyperacoustic frequency. Will use acoustic energy increase skin that the permeability of drug molecule is called phonophoresis or ultrasonic infiltration.
The present invention's part is based on the new method of the dermal delivery that passes through increase biomembrane permeability of having developed. According to some aspect, physically change described film and reach described permeability thereby can pass the artificial opening of the described film of one deck at least or passage by formation. These openings can provide fluid connection or pass the passage of film. For example, when described biomembrane is the cuticula skin layer, the opening of described formation can provide the epidermis that enters below the cuticula and corium skin histology moisture active layer passage or with the fluid connection of described moisture active layer. For this reason, these openings or micropore can be able to be considered as containing the passage of aquaporin or formation, by its not only the permeable membrane thing can spread, and pumping and sucking liquid body, the liquid that can send in microparticle or the individuality can be exuded to skin surface. Amphicheirality by utilizing liquid flow and the micropore of the type, one aspect of the present invention provide improved device, the system and method sent through skin permeable membrane thing as detailed below.
According to aspects of the present invention, provide the paster or the system that comprise paster and perforator, the individual biomembranous passage that passes through that is used to make bioactivator pass through at least one formation flows into individuality.Described paster comprises substrate.Described substrate has and is adapted to contact biomembranous surface and described substrate and also is adapted to absorb or otherwise accepts the biological moisture that passes through biomembranous passage from least one formation.The permeable membrane compositions is placed in the substrate.Described permeable membrane compositions comprises undissolved hydrophilic permeable membrane thing, and wherein said hydrophilic permeable membrane thing can comprise at least a bioactivator, and comprises at least a permeability reinforcing agent such as the pH controlling agent.In one embodiment, the hydrophilic permeable membrane thing with the permeable membrane compositions is delivered to individuality.In another embodiment, hydrophilic permeable membrane thing and the permeability reinforcing agent with the permeable membrane compositions all is delivered to individuality.In some aspects, described bioactivator also can provide the function of at least a permeability reinforcing agent.
In one embodiment, when the bottom surface with described paster place with at least one formation pass the fluid connection of individual biomembranous passage the time, described permeable membrane compositions can contact with the biological moisture such as subcutaneous fluid.In another embodiment,, and also have permeability reinforcing agent in some cases to small part to the undissolved hydrophilic permeable membrane thing of small part, can be dissolved in contact from the biological moisture of individuality or form suspension therein.By this explain do not limit, in one embodiment, contact with permeable membrane compositions in the substrate in case it is believed that the moisture of effective dose, the permeable membrane thing that liquid provides diffusion path to be used near small part is subsequently sent back individuality through biomembrane.On the other hand but and unrestricted, described permeable membrane compositions can have the affinity to subcutaneous fluid, when the bottom surface of paster being placed fluid connection with the passage that passes the individual's skin layer of at least one formation, can extract the subcutaneous fluid of effective dose to the permeable membrane compositions of small part from individuality with box lunch.
In one embodiment, described substrate has and is adapted to contact biomembranous surface, and when the fluid connection that paster placed with the passage of at least one formation, described substrate also is adapted to absorb or otherwise accepts the biological moisture that passes through biomembranous passage from least one formation.Described substrate can comprise at least a polymer and can comprise two or more polymer.Described polymer (polymer) or polymer (polymers) can be water-soluble polymer or insoluble polymer.Single-matrix can comprise water-soluble polymer and insoluble polymer.The limiting examples of water-soluble polymer comprises Polyethylene Glycol (PEG or PEO or POE), polyvinyl alcohol (PVA or PVOH) and polyvinylpyrrolidone (PVP).The limiting examples of insoluble polymer comprises ethane-acetic acid ethyenyl ester (EVA) and ethyl cellulose (EC).Described host material is passable, aspect exemplary and unrestricted, the about 1 weight % that occupies paster comprises other amounts of about 25 weight % of paster, about 30 weight %, about 35 weight %, about 40 weight %, about 45 weight %, about 50 weight %, about 55 weight %, about 60 weight %, about 65 weight %, about 70 weight %, about 75 weight % and about 80 weight to about 99 weight %.In addition, described host material can account for any amount in any weight percentage ranges that derives from these numerical value.For example, aspect exemplary and unrestricted, described host material can be in the scope of the about 60 weight % of about 1-of paster, in the scope of the about 60 weight % of about 20-of paster, in the scope of the about 40 weight % of about 20-of paster or even the scope of the about 40 weight % of about 1%-of paster in.
According to aspects of the present invention, described substrate can comprise the combination of insoluble polymer material or polymeric material.For example and also unrestricted, on the one hand, described substrate can comprise ethane-acetic acid ethyenyl ester (EVA) copolymer, ethyl cellulose (EC), polyethylene, polyethyl acrylate and the copolymer of ethylene and ethyl acrylate and above combination in any.On the one hand, described substrate can comprise vinyl-vinyl acetate copolymer, described copolymer has the relative percentage of the vinyl acetate of scope from 0% to about 60%, comprise other vinyl acetate percentage ratios of about 0%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% and 60%, and any percentage range that derives from these numerical value.Still on the other hand, described vinyl-vinyl acetate copolymer comprises about 40% vinyl acetate.
Sum up as mentioned, described permeable membrane compositions comprises at least a hydrophilic permeable membrane thing, and wherein said hydrophilic permeable membrane thing can comprise at least a bioactivator and at least a permeability reinforcing agent, such as but not limited to, the pH controlling agent.In certain embodiments, described hydrophilic permeable membrane thing simultaneously (with its effect) or play a role as the permeability reinforcing agent independently as the permeable membrane thing.In addition, described permeable membrane compositions can randomly comprise the additive that one or more are suitable for administration.For example, described permeable membrane thing can randomly also comprise the dissolubility controlling agent, filler (in some cases, it can be called as the biocompatibility filler), or any other conventional known material that is suitable for providing or strengthening the dermal delivery of required permeable membrane thing.The example of dissolubility controlling agent and filler can be described subsequently.On the one hand, described hydrophilic permeable membrane thing can account for about 1 weight % of paster to about 99 weight %, comprise other amounts of about 5 weight % of paster, about 10 weight %, about 15 weight %, about 20 weight %, about 25 weight %, about 30 weight %, about 35 weight %, about 40 weight %, about 45 weight %, about 50 weight %, about 55 weight %, about 60 weight %, about 65 weight %, about 70 weight % and about 75 weight %, and comprise any weight percentage ranges that derives from these numerical value.
" bioactivator " comprises any medicine, chemicals or the biomaterial that causes required biological effect or materia medica effect as used herein.Described effect can be partial, and partial anesthetic action for example is provided, and perhaps can be systematic.These materials comprise the wide range of types that is delivered to usually in the intravital chemical compound, and described sending comprises by body surface and film, comprises skin.For this reason, on the one hand, described bioactivator can be micromolecule reagent.On the other hand, described bioactivator can be macromole reagent.Usually, and also unrestricted, exemplary bioactivator includes but not limited to, anti-infective, for example antibiotic and antiviral agent; Analgesics and analgesics combination; The loss of appetite medicine; Anthelmintic; Antirheumatic; Anti-asthmatic agent; Anticonvulsant; Antidepressants; Antidiabetic drug; Diarrhea; Antihistaminic; Antiinflammatory; The antimigraine preparation; The resisting emesis medicine; Antineoplastic agent; Anti-angiogenic hypertrophy medicine; Antiparkinsonism drug; Antipruritic; Psychosis; Antipyretic; Separate the spasm medicine; Anticholinergic; Sympathomimetic; Xanthine derivative; Cardiovascular preparation comprises potassium and calcium channel blocker, beta-blocker, alpha blocker and anti-arrhythmic; Antihypertensive; Diuretic and antidiuretic; Vasodilation comprises general coronary artery vasodilator, peripheral vasodilator and cerebral vasodilation medicine; Central nervous system stimulant; Vasoconstrictor; Cough and cold-treating preparation comprise Decongestant; Hormones, for example estradiol and other steroid comprise corticosteroid; Sleeping pill; Immunosuppressant; Muscle relaxant; Parasympatholytic; Psychostimulant; Tranquilizer (sedatives); Tranquilizer (tranquilizers); Anti-fibromyalgia medicine; Antipsoriatic; Bone resorption inhibitor; Set up the medicament of bone strength; Reduce the brittle medicament of bone; Anti-incontinence medicine; Antisterility disease medicine; Anti-acromegaly medicine; Antihydropic; The anti-obesity medicine; Bone resorption inhibitor; Anesthetis; Antianxiety drugs (anti-anxiety drugs); Tranquilizer; Muscle relaxant; Acetylcholinesteraseinhibitors inhibitors; ACE inhibitor; Anticoagulant; Narcotics; The anti-medicine that forces; Anti-bulimia nervosa medicine; The anti-emetic; Antianxiety drugs (anxiolytics); NSAID; Antirheumatic; The hypothyroidism Drug therapy; Nmda receptor antagonist; The nmda receptor agonist; Part nmda receptor agonist; ADHD treatment, spasmolytic, anticonvulsant, migraine preventive drug; The benign prostatauxe medication; Tranquilizer; Opiate; The pulmonary hypertension medicine; Sleeping pill; The osteoporosis medicine; Anti-inflammatory agent; Diabetes glycemic control medicine; The multiple sclerosis medicine; The thrombocytopenia medicine; With the marrow-reconstitution medicine.
According to aspects of the present invention, described bioactivator can comprise one or more peptides, polypeptide, albumen, nucleic acid or because size and electric charge, the existing routine techniques of known utilization is difficult to other macromole of dermal delivery.The macromolecular example that can send according to the present invention includes but not limited to; oligonucleotide; siRNA; RNAi; antisense molecule; the triple helical molecule; the CpG oligomer; enhancer bait (enhancer decoys); antibody; LHRH; the LHRH analog (for example; goserelin (goserelin); leuprorelin (leuprolide); buserelin (buserelin); triptorelin (triptorelin); gonadorelin (gonadorelin), nafarelin (napharelin) and leuprorelin (leuprolide)); GHRH; GHRF; insulin; short islets of langerhans (swashing) element; calcitonin; Sandostatin LAR Depot (octreotide); endorphins; TRH; NT-36 (chemical name: N-[[(s)-4-oxygen-2-azelidinyl]-carbonyl]-L-histidyl--L-prolineamide); liprecin; pituitary hormone is (as HGH; HMG; HCG; desmopressin acetate etc.); follicle luteoids (follicle luteoids); α-ANF; for example releasing factor of somatomedin (GFRF); β-MSH; GH; Somat; Kallidin I; growth hormone; platelet derived growth factor; asparaginase; Bleomycin Sulphate; chymopapain; cholecystokinin; chorionic-gonadotropin hormone; thyroliberin (ACTH); erythropoietin; epoprostenol (anticoagulant); glucagon; hirudin and hirudin analog be hirudin sample peptide (hirulog) for example; hyaluronidase; interleukin II; follicle stimulating hormone (Urofollitropin (FSH) and LH); oxytocin; streptokinase; tissue plasminogen activator; urokinase; vassopressin; Desmopressin; the ACTH analog; ANP; ANP removes inhibitor; the Angiotensin II antagonist; the vassopressin agonist; the vassopressin antagonist; brad ykinin antagonists; CD4; Ceredase (ceredase); CSI ' s; enkephalin; the FAB fragment; the IgE inhibitor peptides; IGFI; neurotrophic factor; colony stimulating factor; parathyroid hormone and agonist; pth antagonist; prostaglandin antagonists; cytokine; lymphokine; pentigetide (pentigetide); PROTEIN C; Protein S; renin inhibitor; extrasin alpha-I; thrombolytic; TNF; GCSF; EPO; PTH; heparin; low molecular weight heparin; Enoxaparin (Lovenox or Clexane); synthetic heparin; vaccine; vassopressin antagonist analog; interferon-' alpha '; interferon-beta and interferon-; α-I antitrypsin (recombinant) and TGF-β.Gene; Peptide; Polypeptide; Albumen; Oligonucleotide; Nucleic acid; With polysaccharide, glucagon-like-peptide-1 analog and amylin (Amylin) analog.
Term " peptide " refers to the peptide of any length as used herein, and comprises protein.Term " polypeptide " and " oligopeptide " are not subjected to the restriction of any specific intended size, specific unless otherwise noted size when using in this article.Spendable exemplary peptide includes but not limited to, oxytocin, vassopressin, thyroliberin, epidermal growth factor, prolactin antagonist, luteinizing hormone releasing hormone or Relefact LH-RH, growth hormone, somatotropin releasing factor, insulin, Somat, glucagon, interferon, gastrin, tetra gastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalin, endorphins, angiotensin, feritin, Kallidin I, bacitracin, polymyxin, colistin, tyrocidine, Gramicidin, and synthetic analogues, modify and pharmaceutically active fragment, monoclonal antibody and solvable vaccine.Consider that for spendable peptide or proteinic unique restriction be functional restriction.
Contain the peptide of one or more amino and the example of pharmaceutical grade protein and include but not limited to anticarcinogen, anti-angiogenic agent, short angiogenic agent, antibiotic, the anti-emetic, antiviral agent, antiinflammatory and analgesics, anesthetis, antiulcer agent, be used for the treatment of hypertensive medicament, the medicament that is used for the treatment of hypercalcemia, be used for the treatment of the medicament of hyperlipemia etc., more than each contains a primary amine at least in molecule, secondary amine or tertiary amine group, preferably, can mention peptide, protein or enzyme, for example insulin, calcitonin, growth hormone, granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), bone morphogenetic protein (BMP), interferon, interleukin, platelet derived growth factor (PDGF), VEGF (VEGF), fibroblast growth factor (FGF), nerve growth factor (NGF), urokinase etc.
If desired, described bioactivator can be used as and not dissolve anhydrous hydrophilic salts and be present in and send in the storage storehouse.For this reason, " hydrophilic salt " and similar terms include but not limited to the ionic species of bioactivator, medicine or medicament as used herein, the sodium salt of for example described bioactivator, medicine or medicament, potassium salt, ammonium salt, trimethylamine (trimethamine) salt or other cationic salts, the sulphuric acid hydrochlorate of bioactivator, medicine or medicament or other anion salt, the acid-addition salts of alkalescent medicine and the base addition salts of acidic drug.The exemplary example of these salt comprises diclofenac sodium, sodium cromoglicate, Acyclovir Sodium, sodium ampicillin, warfarin sodium, ketorolac tromethamine, amiloride hydrochloride, ephedrine hydrochloride, loxapine hydrochloride, the hydrochloric acid tiotixene, the hydrochloric acid trifluoro draws the Qin (trifluoperizine HCl), Naltrexone Hydrochloride, naloxone hydrochloride, nalbuphlne hydrochloride (nalbuphine HCl), buspirone hydrochloride, hydrochloric acid bupriprion, phenylephrine hydrochloride, Benzazoline Hydrochloride, chlorphenamine maleate, phenylpropanolamine HC1, the hydrochloric acid clonidine, dextromethorphan hydrobromide, metroprolol succinate, spectinomycin hydrochloride, adrenaline acid tartrate, ketotifen fumarate (ketotofin fumarate), atropine sulfate, the citric acid fentanyl, tramadol hydrochloride, the sulphuric acid apomorphine, propranolol hydrochloride, the hydrochloric acid pindolol, lidocaine hydrochloride, quadracycline, tetramycin hydrochloride, tetracaine hydrochloride, cinchocaine hydrochloride, terbutaline sulphate, scopolamine hydrobromide, brompheniramine maleate and dihydromorphinone hydrochloride.
On the other hand, the exemplary example of these little molecular therapies of described bioactivator can be the micromolecule treatment. comprises A Quting (Acitretin) (Soriatane); Amitriptyline (Amitriptyline) (Elavil); Alendronate sodium; Aripiprazole (Arpiprazole) (Abilify); Hydrochloric acid skin Sai Keling (Bethanecol HCl) (urecholine (Urecholine)); Bromocriptine (Bromocriptine) (Parlodel); Bumetanide (Bumetanide) (Bumex); Bupivacaine (Marcaine); Buprenorphine (Buprenex); Buspirone (BuSpar); Cetirizine Hydrochloride; Citalopram (Citalopram) (Celexa); Clorazepate (Chlorazepate) (Tranxene); Clomipramine hydrochloride (Clomipramine HCl); Cyclobenzaprine (Flexeril); Donepezil (Donepezil) (Aracept); Doxazosin (Doxazosin) (can how China (Cardura)); Enalapril (Enalapril) (Vasotec); Enoxaparin (Lovenox); Escitalopram (Escitalopram) (coming scholar general (Lexapro)); Felodipine (Plendil); Fentanyl (Sublimaze; Duragesic); Prozac (Fluoxetine) (Prozac (Prozac); Sarafem); Fosinipril; Galanthamine hydrobromide (Reminyl; Razadyne ER); Glipizide (Glipizide XL (Glucotrol)); Granisetron (Granisetron) (Kytril (Kytril)); Haloperole (haloperidol decanoate (Haldol)); Hycodan; Hydrocortisone acetate; Hydroxyzine hydrochloride; Isradipine (DynaCirc); Ketorolac (Acular (Acular); Toradol); Leflunomide (Arava); Levothyrocine (Levoxyl; Levothroid; Synthroid); Lisinopril (Lisinopril) (Prinivil; Zestril (Zestril)); Tavor (Lorazepan) (Ativan); Loxapine (Loxapine) (Loxitane); Meloxicam (Meloxicam) (Mobic (Mobic)); Memantine (Memantine) (Namemda); Methylphenidate (ritalin (Ritalin); Be absorbed in and reach (Concerta)); Methimazole (methimazol (Tapazole)); Metoclopramide (Reglan); Metolazone (Mykrox; Zaroxolyn); Mirtazapine (Mirtazapine) (Remeron (Remeron)); Montelukast (Montelukast); Nalbuphine (Nalbuphine) (Nubain); Neostigmine (prostigmine (Prostigmin)); Psychostyl (Nortriptylene HCl); Olanzapine (Olanzapine) (Zyprexa (Zyprexa)); Ondansetron (Ondansetron) (ondansetron (Zofran)); Oxybutynin chloride (Oxybutynin Chloride) (Ditropan XL); Oxycodone hydrochloride; Oxymorphone (Numorphan); Palonosetron (Palonosetron) (Aloxi); Paliperidone (Paliperidone); The Paliperidone palmitate; Paxil (Paroxetine) (Paxil); Pergolide (Pergolide) (Permax); Fluphenazine (Triaflon); Dilantin sodium; Pramipexole (Pramipexole) (Mirapex); Prochlorperazine (compazine (Compazine)); Procyclidine (kemadrin (Kemadrin)); Promethazine hydrochloride; Propranolol Hydrochloride; Protriptyline (Vivactil); Ramipril (Ramipril); Risperidone (Risperidone) (Risperidal (Risperdal)); Ropinirole (Ropinirole) (Requip); Rosiglitazone (Avandia (Avandia)); Selegiline (Selegiline) (the many pyrroles of miaow (Eldepryl)) (R-(-)-Selegiline Hydrochloride (Deprenylhydrochloride)); Tamsulosin (Tamsulosin) (Flomax); Temazepam (Restoril); Torecan (Torecan); Tiagabine (Tiagabine) (Gabitril); Timolol (Timolol); C16H25NO2 (Tramadol); Treprostinil sodium (Treprostinil sodium) (Remodulin); Tropisetron (Tropisetron) (Novaban); Warfarin sodium; ATI 5923; Zolpidemtar Trate and DPP-4 inhibitor (sitagliptin (sitagliptin) (Jie Nuowei (Januvia)); Vildagliptin (vildagliptin) (Galvus); BMS-477118 (Saxagliptin) (BMS477118); A Luolieting (Alogliptin) (SYR-322); Ground Na Lieting (denagliptin) (Redona); PHX1149; TA-6666; GRC 8200/EMD 675992; MP513; PSN9301; R1579; BI 1356; PF-734200; ALS 2-0426; TS-021; AMG221; ABT-279; SK-0403; KRP-104; SSR162369; ARI2243; S40010; PT-630; SYR-619; E3024; A-899301).
Still on the other hand, described bioactivator can be the therapeutic agent that becomes known for drug administration by injection usually.The exemplary example of these therapeutic agents comprises adenosine, fluorouracil, Alprostadil (Alprostadil), amikacin sulfate, amiodarone, azithromycin, bleomycin, carboplatin, ceftriaxone, ciprofloxacin, cisplatin, dacarbazine, the hydrochloric acid daunomycin, deferoxamine mesylate, desmopressin acetate, dexamethasone sodium phosphate, dipyridamole, doxorubicin hydrochloride, enalaprilat (Enalaprilat), epirubicin hydrochloride, fluconazol, fludarabine phosphate, flumazenil (Flumazenil), fosphenytoin sodium, Granisetron Hydrochloride, haloperidol decanoate, haloperidol, idarubicin hydrochloride, ifosfamide, irinotecan hydrochloride (Irinotecan HCl), the L-cysteine hydrochloride, calcium folinate, leuprorelin acetate (Leuprolide Acetate), depomedroxy progesterone acetate, mesna (Mesna), Methylprednisolone Acetate, metoclopramide, mitoxantrone, noradrenaline bitartrate, octreotide acetate, ondansetron;
Figure BPA00001260572300261
(paclitaxel), oxytocin, Pamidronate Disodium, pancuronium bromide, promethazine hydrochloride, propofol, sulfamethoxazole and trimethoprim, terbutaline sulphate, depo-testosterone, tobramycin,
Figure BPA00001260572300262
(etoposide (Etoposide)), vecuronium bromide, VINCASAR
Figure BPA00001260572300263
(vincristine sulfate), vinorelbine tartrate,
Figure BPA00001260572300264
(streptozotocin), Abraxane, Acthrel, Adensocan, Alimta (Alimta), Amevive, amikacin (Kanamycin A Sulfate), An Zemei (Anzemet), Arimidex (Arimidex), Android (Arixtra), Arnold new (Aromasin), Avastin (Avastin), Avonex, Betaseron, BICNU, Botox (Botox), Campath, Camptosar, Kang Shide (Casodex), CeeNu, think and praise (Cerezyme), Si Zekai (Cetrotide), Ke Pasong (Copaxone), Copegus, cyclophosphamide (Cytoxan), DepoTestosterone, Dobutamine, Doxil, Eligard, Le Shading (Eloxatin), excellent suitable treasured (Elspar), En Bo (Enbrel), Erbitux (Erbitux), Ethyol, Fabrazyme, Fu Shide (Faslodex), Follistim, Fuzeon, Ganirelex (Antagon), strong select (Gemzar), strong person of outstanding talent peaceful (Genotropin), the peaceful Minquick of strong person of outstanding talent, Gleevec, fruit receives sweet smell (Gonal-F), Trastuzumab (Herceptin), Hexalen, excellent grow sturdily suddenly (Humatrope), Xiu Meile (Humira), with U.S. new (Hycamtin), Infergen (Infergen), Infumorph, Intron A (Intron A), Kineret, Kuvan, Lior Intra, Lucentis, Lupron Pediatric, Macugen, Matulane, He Meiqi (Menopur), Mustargen, Myobloc, Nabi-HB, Neumega, Neupogen, Nexavar (Nexavar), promise exhibition (Norditropin), Nutropin, Nutropin AQ, Orencia, Ai Ze (Ovidrel), Pai Luoxin (Pegasys), the happy energy of pendant (Peg-Intron), Pentam, Prograf (Prograf), general stay (Proleukin) only, hundred when admiring (Pulmozyme), Rebetol, Libiee (Rebif), close reach admittedly (Reclast), Refludan, class gram (Remicade), Repronex, Revlimid, Ribapak, Ribavirin, permanent moral (Risperdal Consta), Rituxan, Rodferon-A (Roferon-A), think true (Saizen), kind dragon (Sandostatin LAR), Serostim, Sprycel, Supprelin LA, Suo Tan (Sutent), Synagis, Synthroid, Te Luokai (Tarceva), Da Xina (Tasigna), Tamoxifen, taxotere (Taxotere), Temodar, Tevtropin, Thalomid, Thyrogen, Tobi, Tubersol, Tysabri, Tykerb, ten thousand Mactra sulcatria Deshayess (Velcade), Vesanoid, Vidaza, Vinblastine, Vincristine, Wei Ruide (Viread), Vistide, Vitamin K, Vivitrol, xeloda (Xeloda), select Thailand (Zometa), Advate, Alphanate, Alphanine, Aranesp, Bebulin, Benefix, Epogen, Forteo, Fragmin (Fragmin), Helixate, Hemofil, Humate, Hyate, Koate, Bai Keqi (Kogenate), Leukine, Lovenox, Monoclate, Mononine, Myochrysine, Neulasta, Neumega, Novarel, promise its (Novoseven), Procrit, Profilnine, Raptiva, Rebetron, Recombinate, Refacto, Caverject (Caverject), D.H.E.45, ondansetron (Zofran), Bayrho D, Protropin, Delatestryl, Plenaxis, Hemofil-M, Monarc-M, ProplexT, Hyalgan, Supartz, Synvisc, Ellence, Nuo Leide (Zoladex), (Pergonal) received in the Puge, Carimmune, Gamimune N, Gammagard, Gammar, Iveegam, Panglobulin, Polygam and Venoglobulin.
About 1 weight % that the bioactivator part of permeable membrane compositions can account for total paster weight comprises other amount of the about 5 weight % that account for paster, about 10 weight %, about 15 weight %, about 20 weight %, about 25 weight %, about 30 weight %, about 35 weight %, about 40 weight %, about 45 weight %, about 50 weight %, about 55 weight %, about 60 weight %, about 65 weight %, about 70 weight % and about 75 weight % to about 99 weight %.In addition, described bioactivator can account for the amount in any weight percentage ranges that derives from these numerical value, for example comprise, the amount in the about 30 weight % scopes of amount, about 1-in the about 10 weight % scopes of about 1-or even the about 60 weight % scopes of about 1-in amount.
According to an aspect, the present invention is the paster that comprises Exenatide and at least a penetrating reinforcing agent.Described penetrating reinforcing agent can be any penetrating reinforcing agent as herein described.In specific embodiments, described penetrating reinforcing agent is the pH controlling agent.In specific embodiments, described pH controlling agent is selected from disodium citrate, succinic acid or Tris.In one embodiment, described paster comprises polymeric matrix, and wherein said polymer can be any polymer mentioned above about this paper first aspect.In another embodiment, described paster comprises storage storehouse substrate.In another embodiment still, described paster also comprises the dissolubility controlling agent, and wherein said dissolubility controlling agent can be any dissolubility controlling agent mentioned above about first aspect present invention.In another embodiment still, Exenatide phase that continues medication is delivered to individuality, the wherein said administration phase can be any time mentioned above about first aspect present invention.In specific embodiments, with Exenatide continue to be selected from about 24 hours, about 3 days or about 7 days administration phase be delivered to individuality.
In one embodiment, the permeable membrane compositions that is placed in the substrate can comprise the means of optionally controlling bioenvironmental pH, the biomembranous passage that passes that has at least one formation in the described biotic environment, the means that maybe can comprise the pH that optionally controls the biological moisture that substrate obtains, or its combination.As indicated above, the means of control pH can be the pH controlling agents that is positioned in the substrate.When described with substrate place with at least one formation pass the fluid connection of individual biomembranous passage the time, described pH controlling agent can adapt to and is dissolved in from the biological moisture that individuality obtains.Provide described pH controlling agent to be adjusted to non-physiological pH with the biological moisture of the contact of near small part in substrate and keep the dissolubility of hydrophilic permeable membrane thing, described hydrophilic permeable membrane thing can be the biological example activating agent.In addition, according to some aspect, described pH controlling agent can also continue at least about 12 hours, at least about 18 hours, at least about 24 hours, at least about 3 days or even remain on non-physiological pH at least about the biological moisture that permeable membrane thing administration phase of 7 days will contact.In others, the permeability reinforcing agent can act on continue few to about 1, about 3, about 5, about 7, about 10, about 15, about 20 or about 30 minutes, thereby continue a few hours increase flux by the relevant mechanism of non-pH.In other embodiments, be loaded in bioactivator in the substrate be enough to individually to continue up to and even surpassed 12 hours, 18 hours, 24 hours, at least 3 days or even administration phase of at least 7 days prolongation keep the hole permeability of the passage that forms in the biomembrane.Yet this does not always set up in all cases or for all bioactivators.The method according to this invention and device are definite, the bioenvironmental pH horizontal adjustment that comprises the passage of formation can be left the physiological pH level, thereby strengthen or prolong the permeability of the passage of described formation.Be not intended to be bound by theory, it is believed that the level that bioenvironmental pH or other aspects are remained on except that physiology can postpone the process that interferential reaction is triggered for biomembrane.Another probability is that chelation is worked in the effectiveness of these pH controlling agents.Can both control pH although should be noted that the pH controlling agent, pH control itself may not be that permeability strengthens the mechanism that takes place.In addition, should be understood that the pH controlling agent is one type a permeability reinforcing agent, and all permeability reinforcing agents all are regarded as part of the present invention.
Physiological pH is known as about 7.4 usually.Therefore, non-physiological pH used herein is meant any pH value except that 7.4, comprises being less than or equal to 7.3 pH value or more than or equal to 7.5 pH value., be to be understood that by the existence of pH controlling agent, the required pH level that reaches depends on concrete bioactivator to be sent at least in part for this reason.In some aspects, can select the pH controlling agent to obtain acid non-physiological pH level.For example, acid non-physiological pH scope can be 2-6, comprises about 3,3.5,4,4.5,5,5.5 pH level and any pH horizontal extent that is obtained by these values.Selectively, in other respects, can select the pH controlling agent to obtain alkalescence (basic) or alkalescence (alkaline) non-physiological pH level.For example, alkaline non-physiological pH scope can be 8-10, comprises about 8.5,9 or 9.5 pH level.
Exemplary and the non-limiting instance of the pH controlling agent that is fit to comprises three (methylol) aminomethane (TRIS), three (methylol) methylglycine (TRICINE), 4-(2-ethoxy)-1-piperazine ethyl sulfonic acid (HEPES), N, N-two (2-ethoxy)-2-aminoethyl sulfonic acid (BES), 2-(N-morpholino) ethyl sulfonic acid (MES), imidazoles, 2-amino-2-methyl-1, ammediol (AMPD); Aminoacid, for example lysine, arginine, histidine, aspartic acid, glutamic acid and glycine; Amino sugar, for example glycosamine and galactosamine; Alduronic acid and glycuronic acid, for example glucuronic acid and gluconic acid; Monocarboxylic acid, for example glycolic or lactic acid, dicarboxylic acids, for example tartaric acid, malonic acid, maleic acid, fumaric acid, malic acid, succinic acid and single sodium salt or tricarboxylic acids, for example citric acid and single sodium salt, double sodium salt and trisodium salt; Inorganic salt with buffering character, for example sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium phosphate, sodium bicarbonate and sodium carbonate.
Described pH controlling agent can exist with any amount that can reach required pH level control mentioned above.For example, about 1 weight % that the pH controlling agent part of described permeable membrane compositions can account for total paster weight comprises other amount of about 5 weight % of paster, about 10 weight %, about 15 weight %, about 20 weight %, about 25 weight %, about 30 weight %, about 35 weight %, about 40 weight %, about 45 weight %, about 50 weight %, about 55 weight %, about 60 weight %, about 65 weight %, about 70 weight % and about 75 weight % to about 99 percentage by weights.In addition, described pH controlling agent can account for the amount of any weight percentage ranges that is obtained by these numerical value, for example comprise amount in the about 60 weight % scopes of amount, about 30-in the about 30 weight % scopes of amount, about 1-in the about 10 weight % scopes of about 1-or even the interior amount of the about 60 weight % scopes of about 1-.
According to an aspect, the present invention comprises at least a permeable membrane thing and at least a paster that is selected from the pH controlling agent of succinic acid or Tris.Described permeable membrane thing can be any permeable membrane thing as herein described.In specific embodiments, described permeable membrane thing is selected from insulin, hydromorphone, Exenatide or citric acid fentanyl.In another embodiment, described paster comprises polymeric matrix, and wherein said polymer can be any polymer mentioned above about this paper first aspect.In other embodiments still, described paster comprises permeable membrane thing storage storehouse.In other embodiments still, described permeable membrane thing phase that continues medication is delivered to individuality, the wherein said administration phase can be any period mentioned above about first aspect present invention.In specific embodiments, with the permeable membrane thing continue to be selected from about 24 hours, about 3 days or about 7 days administration phase be delivered to individuality.
In one embodiment, described permeable membrane compositions comprises additive, and wherein said additive can comprise dissolubility controlling agent, filler or the two.Described additive can comprise controlling packet optionally is contained in the speed that the bioactivator in the substrate discharges from described substrate means.The means of the rate of release of control bioactivator from substrate can be the dissolubility controlling agents, and it can control the dissolving of described bioactivator in the biological moisture that substrate obtains.In some aspects, exemplary dissolubility controlling agent can comprise the reagent of optionally controlling the relevant pH value of solution of particular bioactive agent isoelectric point, IP.The pH of solution is remained on the isoelectric point, IP of bioactivator or can be used for minimizing particular bioactive agent such as the dissolubility in the medium of biological moisture near the isoelectric point, IP of bioactivator relatively.According to equilibrium principle, along with the dissolved bioactivator of part is delivered to individuality by the biomembranous passage of passing of at least one formation, can being dissolved in the resulting biological moisture of the bioactivators of remaining other non-dissolving parts in the substrate then.Therefore, by optimizing the relevant required pH value of solution of bioactivator isoelectric point, IP, can optionally control the rate of dissolution of described bioactivator.In this mode, the bioactivator by control section is dissolved in the speed in the biological moisture, can avoid the bullet (bolus) of bioactivator to send or breaks out the delivery curves that (burst) sends and can realize prolonging.For this reason, be to be understood that, according to some aspect of the present invention, thus the pH controlling agent of describing before this paper also can be used as by the bioactivator that is controlled to small part be dissolved in or be suspended in the biological moisture that substrate obtains speed optionally the controlling packet means that are contained in the speed that the bioactivator in the substrate discharges from described substrate bring into play function.In selectable embodiment, the dissolubility controlling agent can be used to keep the high-dissolvability of described bioactivator.In certain embodiments, send, must use polymer or combination of polymers control release from described paster for the medicine that keeps during using at whole paster continuing.
Aspect selectable, described dissolubility controlling agent can be an ionic strength controlling agent of optionally controlling solution ion strength.Those skilled in the art should recognize that particular bioactive agent is in the ionic strength that depends on medium itself such as the dissolubility in the medium of biological moisture at least in part.For this reason,, can reduce the dissolubility of particular bioactive agent, thereby the bullet that suppresses described bioactivator is sent or is broken out and sends by increasing the ionic strength of the biological moisture that substrate obtains.According to equilibrium principle, along with dissolved bioactivator partly is delivered to individuality by the biomembranous passage of passing of at least one formation, bioactivators of remaining other non-dissolving parts can be dissolved in the biological moisture that obtains in the substrate then.In this mode, the bioactivator by control section is dissolved in the speed in the biological moisture, can realize the delivery curves that prolongs.
Can comprise the salt of ionic compound according to the ionic strength controlling agent of this definition, the salt of described ionic compound is by anion and cation composition, thereby product is neutral on the electricity.The salifiable cation of shape includes but not limited to as follows: sodium, potassium, magnesium, ferrum, calcium, ammonium or pyridine.The anion of salt includes but not limited to as follows: acetate, carbonate, chloride ion, citrate, nitrate anion, hydroxyl, phosphate radical or sulfate radical.The ion salt that obtains from anion and cationic combination can include but not limited to sodium citrate (monovalent salt, divalent salts or trivalent salt), potassium phosphate, sodium sulfate, ammonium phosphate or ammonium sulfate, sodium chloride etc.
Still aspect other, the dissolubility controlling agent can be salting-out agents.Salting-out agents can comprise any biocompatible materials, chemical compound or preferably can produce multivalence (highly-water-soluble) salt of the high inonic strength solution that is equivalent to 1M or higher salinity as used herein.For example and and unrestricted, on the one hand, the disodium salt that described salting-out agents can comprise ammonium sulfate, sodium sulfate or potassium sulfate, sodium hydrogen phosphate or dipotassium hydrogen phosphate, sodium phosphate, disodium citrate or trisodium citrate, dicarboxylic acids is sodium succinate for example.
As the salting-out agents of implementing to describe in the scheme are controlled the rate of dissolution of bioactivator in the substrate.Can strengthen or hinder the water solubility of activating agent such as the reagent of buffer and plasticizer.Have been found that some reagent, in the time of in being used in water-insoluble polymeric matrix, because its dissolubility effect can be controlled the rate of dissolution of bioactivator.Hinder the reagent of activating agent water solubility can slow down the rate of dissolution of described activating agent in dissolve medium.
Be to be understood that some water-soluble polymer can be used as dissolubility controlling agent performance function.
Optional dissolubility controlling agent can exist with any amount that can realize bioactivator required rate of dissolution in the biological moisture that substrate obtains.For example, when existing, about 1 weight % that the dissolubility controlling agent part of described permeable membrane compositions can account for total paster weight comprises other amount of about 5 weight % of paster, about 10 weight %, about 15 weight %, about 20 weight %, about 25 weight %, about 30 weight %, about 35 weight %, about 40 weight %, about 45 weight %, about 50 weight %, about 55 weight %, about 60 weight %, about 65 weight %, about 70 weight % and about 75 weight % to about 99 weight %.In addition, described dissolubility controlling agent can account for the amount of any weight percentage ranges that is obtained by these numerical value, for example comprise the amount of the about 60 weight % scopes of amount, about 30-of the about 30 weight % scopes of amount, about 1-of the about 10 weight % scopes of about 1-or even the amount of the about 60 weight % scopes of about 1-.
As indicated above, by the rate of dissolution in the control bioactivator biological moisture that obtain in substrate or that be absorbed into substrate, the bullet that can prevent described bioactivator is sent or is broken out and sends, if wish like this.For this reason, according to aspects of the present invention, can still remain in the delivery curves that realizes prolongation in the substrate by the bioactivator of guaranteeing therapeutic dose after the administration phase of regulation, administration in described regulation is interim, and described substrate has been in the fluid connection with the passage of biomembranous at least one formation.For example, according to some aspect, continued at least 12 hours, at least 18 hours, at least 24 hours, at least 36 hours on surface substrate or even after administration phase of 7 days places fluid connection with the passage of at least one formation, the undissolved bioactivator of therapeutic dose can still remain in the substrate.As indicated above, this remaining therapeutic dose can finally be dissolved in the biological moisture according to the existence of dissolubility controlling agent.Yet, remain in the therapeutic dose in the substrate after the period that rely on to surpass prolongs, can prevent from that bullet from sending or breaking out to send that this provides the ability of the period of realizing that required bioactivator flux is used to prolong.
Should be noted that when needs bullet delivery curves the present invention also can be used for raising and send.In one embodiment, by utilizing invention as herein described, will more effectively send as bullet such as the bioactivator of Enoxaparin and other low molecular weight heparin chemical compounds.At this moment, administration time can be about 5,4,3,2,1 minutes or be less than 1 minute.In selectable embodiment, administration time can be greater than 5 minutes or even greater than 12 hours.
Except that optional dissolubility controlling agent, described permeable membrane compositions also can comprise one or more filleies.Exemplary filler can comprise in excipient, hygroscopic agent, penetrating agent, anti-consolidant, anticoagulant, antiinflammatory, antimicrobial, counter-stimulus, epithelium regeneration inhibitor, nitrogen oxide formation inhibitor, Melanogenesis inhibitor, batching agent, lubricant, plasticizer, wetting agent, the chelating agen etc. any one or multiple.Hydrophilic permeable membrane thing itself also can show the function of one or more above-mentioned filleies.A kind of filler also can show the function more than a kind of above-mentioned filler.For example, and also unrestricted, excipient also can be used as antiinflammatory and/or even hygroscopic agent performance function.Described one or more filleies, when existing, about 1 weight % that can account for paster is to about 99 weight %, comprise other amount of the about 5 weight % as paster, about 10 weight %, about 15 weight %, about 20 weight %, about 25 weight %, about 30 weight %, about 35 weight %, about 40 weight %, about 45 weight %, about 50 weight %, about 55 weight %, about 60 weight %, about 65 weight %, and also comprise any weight percentage ranges that obtains by these numerical value.
Anti-as used herein consolidant for example can comprise, the reagent of anticoagulant, antiinflammatory, inhibition cell migration, epithelium regeneration inhibitor, penetrating agent and salting-out agents.The anticoagulant that is fit to can comprise, for example, and heparin, low molecular weight heparin, synthetic heparin, pentosane polysulfate ester, citric acid, citrate, EDTA and glucosan with 2000 to 10000 Dalton molecular weights.The antiinflammatory that is fit to can comprise, for example, and hydrocortisone sodium phosphate, betamethasone sodium phosphate and omcilon sodium phosphate.The reagent that is fit to that suppresses cell migration can comprise, for example, and laminin and/or its related peptides.
Penetrating agent can be included in any biocompatible materials, chemical compound or the compositions that can produce in the solution greater than about 2000kPa osmotic pressure as used herein, or its mixture.For example and also unrestricted, on the one hand, described penetrating agent can comprise such as the biocompatible salt of sodium chloride or such as the neutral compound of glucose, thus perhaps such as glycine, have sufficiently high concentration produces required osmotic pressure in solution a zwitterionic compound.For example, on the one hand, penetrating agent can produce the osmotic pressure greater than about 2000kPa in solution.On the other hand, penetrating agent can produce the osmotic pressure greater than about 3000kPa.
, be to be understood that aspect selectable, described bioactivator also can provide the function of any or multiple above-mentioned filler for this reason.For example, and also unrestricted, bioactivator also can show above-mentioned anti-healing effect.Particularly, on the one hand, described bioactivator can produce the osmotic pressure greater than about 2000kPa in solution or suspension, so that can suppress the agglutination of the passage that passes individual's skin of at least one formation.
The hygroscopic agent intention comprises biocompatible materials, chemical compound or the compositions that has for the affinity of subcutaneous fluid as used herein, when it is present in the permeable membrane thing with box lunch, can strengthens to be drawn into from the subcutaneous fluid of individuality and send the storage storehouse.For example, and also unrestricted, on the one hand, be mannitol according to the operable suitable hygroscopic agent of the present invention.The interpolation of moisture absorption packing material can also be as the attraction thing for the liquid that oozes out from the skin of handling, assistance causes the storage storehouse with liquid and contacts with bioactivator, effect simultaneously produces more the skin surface side from the storage storehouse to the intravital diffusion admittance in storage storehouse, wherein can enter more bioactivators.Should select these packing materials like this, when being delivered to the dissolving in a single day of intraindividual bioactivator and/or suspending, will reduce to minimum for any inhibition of described bioactivator.
On the one hand, described filler can comprise glycerol, propylene glycol (PG) or its combination.When as the filler of part at least and when being merged in, glycerol and/or propylene glycol can be used as in wetting agent, hygroscopic agent, lubricant, plasticizer, antimicrobial, the penetrating reinforcing agent of skin and/or the counter-stimulus one or more and play a role.In addition, be to be understood that glycerol and propylene glycol also are effective to being used for increasing bioactivator from the rate of release of substrate described herein and the availability of increase bioactivator.When using, glycerol and/or propylene glycol be existing greater than the amount of 0.0 weight % to the scope of about 5.0 weight % with paster approximately usually, the amount that comprises about 0.5 weight %, about 1.0 weight %, about 1.5 weight %, about 2.0 weight %, about 2.5 weight %, about 3.0 weight %, about 3.5 weight %, about 4.0 weight %, about 4.5 weight %, and any range that obtains by above-mentioned percentage by weight.
On the other hand, described filler can be selected like this, makes the pH of the liquid of described filler contact keep acid.This can give inherent antimicrobial acivity at multiple microorganism, and described microorganism includes but not limited to antibacterial, yeast and mycete.In addition, also can in the polymeric film preparation, add the antimicrobial acivity of one or more antimicrobials with the described film of further enhancing.
In one embodiment, provide according to exemplary paster that comprises perforator and paster of the present invention or system and caused that the permeable membrane thing flows into intraindividual method by the percutaneous of the passage that passes the individual's skin layer of at least one formation.On the one hand, described method comprises provides the individuality with percutaneous permeable membrane thing medicine-feeding part, and described percutaneous permeable membrane thing medicine-feeding part comprises the biomembranous passage such as skin layer of passing of at least one formation.As indicated above, described individuality can be for having at least one biomembranous any lived biology, and bioactivator can pass the film formed passage of this biology by at least one and send or administration.Exemplary individuality can be a mammal, for example, and people for example.Aspect selectable, described individuality can be a nonmammalian.Still on the other hand, method and system of the present invention can be used on the plant.
Be to be understood that, putting into practice when of the present invention, use the storage stability that contains anhydrous storage storehouse design can the improvement product that does not dissolve the permeable membrane thing, reduced in most cases demand cold preservation.For example, for protein, peptide or vaccine antigen, the ability that need not the stored under refrigeration product is favourable, has eliminated in whole distribution network the needs to cold preservation.For the vaccine paster, this characteristic allows worldwide to provide and deliver vaccine and need not reliable cold supply chain.Use anhydrous formulation also can provide other advantage, comprise the inherent antimicrobial acivity that water-free preparation shows, and the ability that physically less storage storehouse is provided, because do not keep the stable needed essential concentration of permeable membrane thing solution.Should be noted that the present invention also provides embodiment, wherein adjuvant (molecule of for example common non-permeable membrane thing and peptide) and antigen are sent the means of replying as booster immunization expediently jointly in identical paster.
As shown in Figure 1, the device according to one embodiment of the invention comprises the substrate 20 with end face 22 and opposed bottom surface 24.Permeable membrane compositions as indicated above further is positioned in the described substrate.In one embodiment, when the bottom surface with described substrate place with at least one formation pass the fluid connection of individual biomembranous passage the time, comprise hydrophilic permeable membrane thing and can contact with biological moisture with permeable membrane compositions such as the penetrating reinforcing agent of pH controlling agent.In case the biological moisture of effective dose contacts with described substrate, next this moisture be provided for the hydrophilic permeable membrane thing of near small part and randomly send back intraindividual diffusion path through described biomembrane to the penetrating reinforcing agent of small part.For example, on the one hand and also unrestricted, described permeable membrane compositions can have the affinity to subcutaneous fluid, when the bottom surface of described substrate being placed fluid connection with the passage that passes the individual's skin layer of at least one formation with box lunch, to the permeable membrane compositions of small part can be from the described individual subcutaneous fluid that extracts effective dose.Be to be understood that when putting into practice when of the present invention, on the one hand, being positioned over not dissolving hydrophilic permeable membrane thing in the substrate, not have a percutaneous active or be not useable for dermal delivery, when beginning to contact with the subcutaneous fluid that extracts from individuality.In addition, the implantable or oral delivery system of conventional use highly water soluble drugs form experiences explosion type effect (burst effect) usually from the PK curve that obtains.Yet, remain in skin surface by substrate, and provide substrate, hydrophilic permeable membrane thing and such as the penetrating reinforcing agent pH controlling agent, that can guarantee the rate of release stipulated, permeable membrane compositions of the present invention can be eliminated this explosion type effect hydrophilic permeable membrane thing.
One exemplary aspect, can make up and arrange described substrate like this, make described substrate have the porous that defines a plurality of pipelines that interconnect, at least a portion in wherein said a plurality of pipelines is communicated with the substrate bottom surface.This aspect of root a tree name, undissolved hydrophilic permeable membrane thing and randomly can being placed at least a portion in a plurality of pipelines of substrate such as the penetrating reinforcing agent of pH controlling agent.Thereby this exemplary substrates be adapted to use by at least one formation pass biological moisture that biomembranous passage extracts dissolve or suspend be positioned over described intramatrical to small part permeable membrane thing and randomly such as the penetrating reinforcing agent of pH controlling agent, thereby make dissolved reagent by biomembrane and enter diffusion or transhipment in the individuality.
Different transporting mechanisms can influence described permeable membrane compositions from dispersion and the motion of substrate in skin histology.In one embodiment, be positioned over permeable membrane thing in the substrate in case by breaking away from the microparticle form and become solution or suspension usually around in the tissue when discharging, this permeable membrane thing can be by biological utilisation.In case in solution or suspension, diffusion can think that microparticle permeable membrane thing provides the outer of percutaneous processing and enters or pass active layer and enter intraindividual transporting mechanism.Along with this process continuing in time carries out, leave paster and move into the formed space of permeable membrane thing in the skin, formed the passage that penetrates in the matrix body, arrive than the additional channels that is present in the more permeable membrane thing of permeable membrane thing of stromal surface at first thereby provide.Thereby by substrate being placed and being communicated with of the passage that passes the individual's skin layer of at least one formation, subcutaneous fluid can provide the hydration of effective dose or effect level for substrate, thus the dissolving or the described permeable membrane thing that suspends.Like this, can provide the permeable membrane thing of relative higher concentration in solution or the suspension, described solution or suspension also are communicated with active mass's layer of skin.Should be noted that once more can be at any one of this process and described all processes of whole the application, a plurality of or permeable membrane thing of following in steps such as the penetrating reinforcing agent of pH controlling agent.
By forming according to paster of the present invention, should recognize, realize before this by become known for conventional transdermal delivery device that percutaneous permeable membrane thing sends, system and method the high-caliber relatively permeable membrane thing availability that can't realize be possible.Conventional seldom utilize the bioactivator in the paster of being present in that surpasses about 30-40% through skin product.Yet, use conventional retention analysis, delivery matrices of the present invention, on the one hand, about 10% permeable membrane thing availability to about 100% the scope is provided, comprises about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about permeable membrane thing availability of 85%, about 90% and about 95% and comprise any permeable membrane thing availability scope that obtains by these numerical value.
In addition, put into practice and to recognize when of the present invention, according to delivery matrices of the present invention by dissolving constantly or suspend and to be positioned over the intramatrical permeable membrane thing that do not dissolve and can to keep constant, high relatively relatively chemical potential energy driving force, thereby make and the suspension of the channel connection of at least one formation or the administration phase that dissolved permeable membrane thing can remain on saturated level or be used to prolong near saturated level.By using substrate as permeable membrane thing carrier, can with natural instincts but effective porous substrate " filling " space between a plurality of passages that form on the zone of the skin part of processing effectively is retained to minimum with required liquid volume.On the contrary, make the permeable membrane thing enter skin in order to produce same osmotic drive power, compare with the amount of needed permeable membrane thing when the permeable membrane thing exists not dissolve the anhydrous solid form, conventional method and device need the permeable membrane thing of relatively large amount to produce the saturation point condition.Use conventional neat liquid or gluey aqueous formulation, with be to compare when existing when bioactivator except that the solid form that through the water that micropore provides, exists by body without any water, need the bioactivator of big many amounts to make described bioactivator enter skin to cover the skin part of handling and to produce same saturated level driving force.On the one hand, aqueous passage imparting system in the skin that provides in the following manner functional: the outermost layer that changes skin becomes it in the phase of wearing permeable, it is individual that permeable degree is enough to allow subcutaneous fluid to flow out, dissolving or suspended biological activating agent, and allow bioactivator dissolved or that suspend to move in the body then through these same aqueous passages.
Can be known by any routine, be used to provide the means of solid matrix to make delivery matrices of the present invention, described solid matrix has at least a undissolved hydrophilic permeable membrane thing that is positioned over wherein.For example, comprise in the embodiment of polymeric matrix at a delivery apparatus, described polymer and also comprise any permeability reinforcing agent (as the pH controlling agent), dissolubility controlling agent and/or the hydrophilic permeable membrane compositions of optional filler, dry mixed together can to use heat to mediate blender (heatedkneading mixer).If described permeable membrane thing contains a plurality of components, described a plurality of permeable membrane thing components, if desired, can premixing, with guarantee with the permeable membrane thing with form homogenizing permeable membrane compositions before matrix material is mixed.The premixing of this permeable membrane thing if desired, can be carried out on for example conventional impeller.
The temperature of hybrid system is set should be enough high, softening to allow specific polymer, it can be mediated, but should too highly not melt down to described specific permeable membrane thing component.These conditions depend on the particular polymers host material certainly and are positioned over the character of permeable membrane thing wherein.Thereby those skilled in the art need not too much experiment can easily obtain these operating parameters.The heat that obtains can be mediated mixture then and be processed into and comprise for example independent dosage form of the delivery apparatus of cut film, perhaps be shaped to required shape arbitrarily, for example circle, ellipse, rectangle, square or other required shape arbitrarily.
Described permeable membrane thing delivery apparatus also can be made into required thickness arbitrarily, comprise that about 0.01mm is to the interior thickness of the scope of about 30mm, comprise according to appointment 0.05, about 0.1, about 0.5, about 1.0, about 5.0, about 10.0, about 15.0, about 20.0 and about 25.0, perhaps even the thickness in any thickness scope that obtains by these numerical value.For example, described thickness can be at about 0.01mm to the scope of about 10.0mm, perhaps even about 0.5mm extremely in the scope of about 1.0mm., should recognize that required thickness can for example depend on specific matrix components and/or for the required delivery parameter of given permeable membrane compositions delivery apparatus when of the present invention when putting into practice for this reason.For example, on the one hand, it is desirable that the thicker film of sending is provided, and purpose provides the long administration phase.Thereby those skilled in the art only can easily obtain the customization and the optimization of these particular delivery plant bulks by normal experiment.
In one embodiment, can be by this processing of following realization: a certain amount of heat is mediated the thickness of mixture melt extruded for substantially all colluding, and use conventional die-cut method to form the net shape of delivery apparatus then.Selectively, can be by the processing of following realization mixture: the mixture that will heat pushes by mould, form the ribbon of basic evenly width and thickness, by described ribbon is cut into the Len req form, rectangle dosage form for example, perhaps from described ribbon, punch out final dosage form, can cut out delivery apparatus from described ribbon.In one embodiment, on the ribbon that squeezes out, use die-cut method, processing equipment also can be set at " leftover pieces " that the ribbon that stays after the die-cut step is unnecessary and be recovered in the charging of mixing/extruder, thereby realizes for mixing undressed component and forming the processing near zero loss of final device dosage form.
Selectively, the polymer powder that low temperature can be milled mixes the distribution up to the evenly basic and homogenizing that reaches described permeable membrane thing and polymer with permeable membrane thing and other optional components.Then, the final required delivery apparatus shape of mixture hot pressing that obtains or cold moudling or melt-extruded one-tenth.
Still on the other hand, can use conventional solvent cast processing, for example wherein host material is dissolved in the organic solvent, for example dichloromethane, methyl tertiary butyl ether(MTBE), methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, ethanol, acetone or above binary/ternary mixture.Undissolved permeable membrane thing and other optional components can be added in the dissolved polymers host material then and also then the suspension that obtains be irritated to the form with required size and shape.To or otherwise remove such as the solvent evaporation of dichloromethane then so that permeable membrane thing delivery apparatus to be provided.
Should recognize as those skilled in the art, the relative quantity of bioactivator, permeability reinforcing agent (as the pH controlling agent), dissolubility controlling agent, filler component and host material all can be adjusted, and enters individual required flow velocity and required persistent period or effective administration phase so that the permeable membrane thing to be provided.For example, described permeable membrane thing can comprise the filler component of the relevant amount of bioactivator scheduled volume, the agent of for example preparing burden, and this can provide the predetermined transdermal dosage of bioactivator.Selectively, described permeable membrane compositions itself can exist with solid matrix scheduled volume relevant amount and composition, and this can provide the set rate of body percutaneous permeable membrane diffusion.
On the one hand, be designed to provide following required statistics probability with the concentration of not dissolving the permeable membrane thing that is positioned in the anhydrous storage storehouse: when being exposed to the moisture source, for example be exposed to the subcutaneous fluid that micropore obtained from skin, this moisture undissolved permeable membrane thing that will dissolve or suspend, so that the development of aqueous passage enters in the substrate and passes substrate, spread all over substrate gradually and form, until need having dissolved by the permeable membrane thing that micropore is delivered to individual aequum or suspend and by these passages, spreading and diffuse in the individual's skin by micropore.By selecting proper proportion, can make up such substrate: form the aqueous passage when the liquid forward position little by little further moves into described substrate, described substrate guarantees that basic all intramatrical permeable membrane things all can contact by these aqueous passages.
In addition, can comprise optional dissolubility controlling agent and/or filler in the device, with the rate of release of control bioactivator, improve bioactivator in skin histology dissolubility, inhibition or strengthen in the affected tissue selected physiological phenomenon etc., described selected physiological phenomenon such as but not limited to, booster immunization is replied, inflammation-inhibiting is replied, edema or erythema, keeps the pH scope of regulation in the tissue.For this reason, by making up delivery apparatus so that the more limited rate of release of minimum speed limit than skin histology organism-absorbing activating agent to be provided, can make described system repeatability very good, need not to consider to influence usually in delivery rate individual of bioactivator or the variability between individuality.
In one embodiment, can control medicine by interpolation multiple polymers kind discharges from substrate.These polymer can influence the porous of described substrate, thereby the restriction interstitial fluid is for the availability of permeable membrane thing or permeability reinforcing agent and therefore the control that permeable membrane thing and/or permeability reinforcing agent are sent is provided.These polymer particularly during the polymer of water solublity kind, thereby can also limit interstitial fluid for the availability of permeable membrane thing and/or permeability reinforcing agent and control them and discharge from film.For example, permeable membrane thing or the required interstitial fluid of permeability reinforcing agent dissolving can partly be consumed by the dissolving of water-soluble polymer, thereby control sending of other water solublity kinds effectively.Selectively, the dissolving of water-soluble polymer can cause the viscosity of membrane environment to increase, and this also can be used as control and sends or dissolved means.Selectively, the dissolving of polymer can cause such membrane environment, and wherein the valid density of permeable membrane thing or permeability reinforcing agent is lower than the valid density when not having dissolved polymer, thereby reduces delivery rate.
Should also be appreciated that device of the present invention is not limited to comprise the aspect of single delivery patch, comprise the embodiment of a plurality of delivery patch in addition.For example, as depicted in figure 3, on the one hand, device of the present invention can comprise a plurality of delivery matrices or the storage storehouse of piling up arrangement.As shown in the figure, delivery matrices or storage storehouse 20 can comprise, such as but not limited to, pile up three permeable membrane thing delivery matrices (or storage storehouse) of arrangement, 20 (a), 20 (b) and 20 (c).
Selectively, can comprise according to device of the present invention and be in adjacent or a plurality of substrate of side by side relationship.Still on the other hand, can comprise the combination of a plurality of substrate of piling up and a plurality of adjacent delivery matrices according to device of the present invention.By multiwalled a plurality of delivery matrices is provided, wherein because the dissolving forward position is in turn to arrive each layer, so the rate of release of being scheduled in the administration phase at predetermined permeable membrane thing can change, thereby makes those skilled in the art can adjust the PK curve of permeable membrane thing in the individuality that obtains.For example, on the one hand, can provide a plurality of delivery matrices, wherein at least two substrate comprise different size characteristics.On the other hand, can provide at least two substrate, each substrate has the different permeable membrane compositions that is positioned over wherein.Still on the other hand, considering to provide a plurality of delivery matrices, and each in wherein said a plurality of substrate comprises different permeable membrane compositions.
Still on the other hand, can arrange a plurality of permeable membrane thing delivery matrices so that predetermined pulsating bioactivator delivery modality to be provided.This pattern can realize with fully passive diffusion system, wherein makes up delivery matrices with a plurality of hypothalluses, contains the permeable membrane thing in some layer and does not contain in some layer.Therefore, when the solution forward position moved through substrate, only those periods when the layer that contains bioactivator is in the edge in solution forward position, described bioactivator just can be sent.The biological activity agent content that customizes in these multilamellars provides the transdermal delivery system that influx can be adjusted to optimum.For example, insulin can be sent system constructing is the natural rhythm and pace of moving things cycle that meets individual glucose metabolism, thereby changes the amount of the bioactivator of sending in the administration phase in the mode of sequencing, thereby better treatment is provided.
Provide other method of permeable membrane thing rate of release control to include but not limited to, change the physical Design of substrate, when changing the dissolving forward position and moving in the substrate formed diffusion path flexibility, select anhydrous polymer or other host material, perhaps by adding the particular rate restriction scheme in the substrate, for example specific film or layer.In one embodiment, polymeric matrix can be configured as the particular texture that has on the skin contact surface, designing described texture is in order to increase the surface area of skin contact surface.By increasing the surface area between substrate and the skin, the initial rate that bioactivator discharges into the liquid surface between paster and the micropore will be bigger, and this causes the higher initial flux of bioactivator.When the bioactivator of close grain surface in the substrate is exhausted, and penetrate into aqueous porous in the polymeric matrix when deeper extending in the substrate, because it is farther that the effect of the surface area that increases weakens, dissolves in the forward position immigration matrix body, flowing of bioactivator will slow down.Exemplary surface area increase method can include but not limited to, wrinkling, punch, extend to a series of holes in the substrate, described hole or part are passed or are passed completely through or hole partly and the combination in hole completely, and the hole of described part all is positioned at the same degree of depth or is positioned at the various degree of depth.Basic, the physics that the surface area of the dissolubility liquid that provides by micropore is provided in any change is shaped and all can be used for adjusting the flux of different time points in the phase of wearing.Some processes that can be used for forming in this mode substrate include but not limited to, extruding, punching press, cast, punching, die-cut, roll-in, fusion, Laser Processing, mill, etching or generation process, or the combination in any of said process.The veining of these layers mesostroma and puncture not only can be applicable to place the layer of skin surface, also can be applicable to be clipped in the interior layer between other layer.With reference to Fig. 2, described an exemplary delivery substrate that contains the floor space of increase among the figure.As shown in the figure, delivery matrices 20 (d) can comprise veined bottom surface 22, and wherein said veined surface comprises a series of line style hole 28.
Put into practice and should recognize when of the present invention, device as herein described can be used for continuing the administration phase dermal delivery permeable membrane thing that prolongs.For this reason, the administration phase that delivery matrices as herein described can be used for continuing to be scheduled to arrives permeable membrane thing dermal delivery individual, described predetermined administration phase scope from about 5 minutes until about 400 hours or longer, comprise about 1,5,10,12,15,18,20,24,30,36,45 and 50 minute and about 1,5,9,10,12,15,18,20,24,30,36,45,50,100,150,200,250,300 and 350 hour administration phase.Selectively, device of the present invention was used in about 5 minutes to about 1 hour, about 1 hour to about 6 hours, about 6 to about 12 hours, about 12 to about 30 hours, about 30 to about 50 hours, about 50 to about 80 hours, about 80 to about 120 hours and even the about 120 permeable membrane things to about 180 hours predetermined interim dermal delivery scheduled volume of administration.In other embodiments, device of the present invention was used in about 1 day, about 3 days or the permeable membrane thing of about 7 days predetermined interim dermal delivery scheduled volume of administration.
For this reason, when being not intended to be bound by theory, in some aspects, the relatively long administration phase that device of the present invention is realized may be the result of hyperosmosis diffusion gradient, and described hyperosmosis diffusion gradient comes from the time period that prolongs permeable membrane thing dissolved or suspension is remained near saturation point.Think that also these high relatively osmotic pressure gradients itself can provide the influence for the anti-healing of the passage that passes individual's skin layer opening that forms, further strengthened the ability that realizes the administration phase of prolongation.Thus, should recognize, can make up and arrange delivery apparatus of the present invention to send the permeable membrane thing of predeterminated level in order to continue almost any required administration phase.
Exemplary means according to one aspect of the invention is depicted in Fig. 4.As shown in the figure, this exemplary means provides the transdermal patch assembling, and it comprises as described earlier in this article delivery matrices or storage storehouse 20.Described delivery matrices is fabricated and is arranged to has end face and opposed bottom surface.Backing supporting layer 30 has inside facing surfaces, and it is connected in the end face of delivery matrices at least in part.On the one hand, for delivery matrices removably being attached on the individual skin, the size of backing supporting layer and shape can being made to stretch out and exceed delivery matrices.In addition, the inside facing surfaces to small part of described outward extending backing supporting layer also can contain adhesive phase placed thereon 50.Should recognize that as those skilled in the art the adhesive phase of placing can provide the adhesion connected system of periphery at least a portion of the backing layer that extends beyond the substrate periphery.
Selectively, also consider and to design described delivery matrices, make it have skin contact surface enough sticking, that can removably directly adhere to individual skin.This can make the overall size of paster minimize and reduce to keeping enough viscosity paster (for example 1,2,3 or 7 day) during paster is worn is sticked on the skin dependence for the periphery binding agent.When putting into practice invention disclosed herein, should recognize, can be by for example optimizing the percentage ratio of polymer, hydrophilic permeable membrane thing and/or permeability reinforcing agent, and optimize production process parameters and obtain this substrate.Those skilled in the art need not too much experiment can determine this optimization.
On the one hand, backing supporting layer 30 can be a base closed at least.Selectively, described backing supporting layer can be permeable to small part half.For this reason, in some cases, half permeable backing, for example 3M
Figure BPA00001260572300431
Product can provide more user comfort as the permeable backing of steam, and the permeable backing of described steam has higher user toleration growing the phase of wearing usually.In addition, the half permeable backing supporting layer that has a specific average steam conduction velocity (MVTR) by design is controlled the water transport velocity by film, and the may command medicine enters the rate of release of skin.In other cases; more fully Feng Bi backing can be preferred, and purpose is to guarantee that substrate is from available from the subcutaneous fluid of the passage of paster assembling at least one formation down and from by around the passage that forms and the maximization hydration of losing through epidermis water of the intact skin between the passage of formation.Selectively, thus described backing can be made as complete closed with the hydration that promotes film and with the contacting of subcutaneous fluid, and that the binding agent of periphery can be made into is half permeable to allow better to wear characteristic, for example better adhesiveness and/or littler stimulation.
Described paster assembling also can comprise the anti-releasing layer 40 that can throw off, and its size and shape are made as the bottom surface to small part of protection delivery matrices and avoid the environmental element influence, will be used up to this device.On the one hand, described anti-releasing layer can removably be fixed in the backing supporting layer that extends to the periphery of small part, and described backing supporting layer has adhesive phase placed thereon.As what be to be understood that, not only provide protection according to the location of the releasing layer of this aspect for the bottom surface of delivery matrices, can also further add the adhesive phase of protective layer to the periphery extension that is positioned over the backing supporting layer.Then, the paster assembling that comprises delivery matrices, backing supporting layer, adhesive phase and anti-releasing layer can be placed independent bag and hermetically closing.
In one embodiment, provide the method that causes permeable membrane thing percutaneous inflow individuality according to exemplary delivery substrate of the present invention by the passage that passes the individual's skin layer of at least one formation.On the one hand, described method comprises provides the individuality with percutaneous permeable membrane thing medicine-feeding part, and described medicine-feeding part comprises the passage that passes skin layer of at least one formation.As used herein, described individuality can be any lived biology with skin layer that at least one can the administration of percutaneous permeable membrane thing.For this reason, described individuality can be a mammal, for example, for example, individual human.Aspect selectable, described individuality can be a nonmammalian.Still on the other hand, method and system of the present invention can be used for plant.
Described percutaneous permeable membrane thing medicine-feeding part is made up of the passage that passes the individual's skin layer that at least one forms.Described passage can be by any at present known means formation that is used to provide the passage that passes the individual's skin layer.For this reason, skin treatment can be that certain forms the one or more little artificial openings or the method for micropore in skin, the size range of described artificial opening or micropore is, the span of 1-1000 micron, comprise about 1 to about 500, about 100 to about 1000, about 200 to about 600 and about 400 to about 800 microns span, and the degree of depth of 1-500 micron, comprise about 1 to about 100, about 50 to about 100, about 70 to about 90, about 20 to about 80, about 100 to about 400, about 200 to about 300 and about 250 to about 500 microns degree of depth, fluid connection between the skin activity cellular layer under the skin outermost layer of described artificial opening or micropore permission bioactivator or substrate and biology, the skin outermost layer of described biology is people's horny layer usually.These micropores can allow subcutaneous fluid to be exuded to the surface of skin by micropore.
Aspect exemplary, but be not the intention restriction, can be by using the hot piercing device, with microneedle, blade (lancets) or the mechanical skin puncture of blade (blades), laser ablation, radio frequency or electricity melt, electroparacentesis or melt and/or hydraulic jet forms individual's skin interior micropore or passage.Creating passage by mechanical means comprises and uses the ridge skin puncture or the scraping of solid microneedle for example or " bullet " to pass cuticular path or approach.Skin treatment also can include but not limited to, makes the suitably permeable method of skin below for example: the supersound process of application of sonic energy or skin is peeled off or is denuded processings, gas with the permeability, electroporation, tape stripping (tape stripping), the abrasion that improve skin and sprays abrasion processing, micropuncture, chemical treatment, heat treatment or mechanical treatment by such as the described device of PowderJectPharmaceutical PLC dermal application high speed inert particle being carried out.The example system, device and method that are used to form required micropore be at U.S. Patent application the 5th, 885, No. 211, the 6th, 527, No. 716, the 6th, 597, No. 794, the 6th, 611, No. 707, the 6th, 692, No. 456, the 6th, 708, No. 060 and the 6th, 711, discuss in No. 435 and U.S. Patent application 2004-0220456 number, 2004-0039342 number and 2004-0039343 number, by reference Yi Shang full text and incorporate it into this paper.
Remove after the anti-releasing layer, can place the paster assembling on the individual's skin in the following manner then: the bottom surface with delivery matrices be positioned permeable membrane thing medicine-feeding part altogether at least basically, as described herein, described permeable membrane thing medicine-feeding part has the passage that passes the individual's skin layer of at least one formation, thereby the permeable membrane thing delivery matrices that contains undissolved hydrophilic permeable membrane thing is in the fluid connection with the passage that passes the individual's skin layer of at least one formation.Simplification is positioned the active region of paster the system design that the whole bag of tricks on the skin part of micropunch can be integrated with integration altogether, for example, for example use the system that stays visible mark after the micropunch method, thereby when using these signs, allow user paster can be placed correct position as reference point.Serviceable indicia forms these signs, and described labelling perhaps even by the mechanical texture that stays interim figure on skin forms these signs simply such as but not limited to dyestuff or ink; The doubling co-location system, wherein paster is connected in perforation system in the following manner provisionally: when finish perforation and with perforation system when skin part is removed, stay little " hinge " assembly and support paster, when spending, guarantee required common location with convenient doubling paster and described hinge warpage 180; After removing perforation system, the locating ring of periphery indicant is left on the skin, and this locating ring provides the required guiding of correct placement paster; Use full automatic applicator system, it uses perforation system according to priority, perforation system is removed, and then with for user transparent fully and randomly in addition the mode of hiding use paster; Use fully integrated system, wherein the perforator assembly is biocompatible, is the skin side that is integrated directly into paster, and is designed to after finishing perforation procedure, allows described perforator assembly to be left on position facing to the skin of below, storage storehouse.Therefore, in one embodiment, described perforator is enough porous, allowing entering the storage storehouse from the required liquid flux of micropore, and allow from the dissolved of substrate or the bioactivator that suspends return near the perforator/pass perforator to go forward side by side into micropore.
In one embodiment, described permeable membrane thing delivery matrices keeps the fluid connection with the passage of at least one formation, thus the passage by at least one formation from individuality extract the subcutaneous fluid of effective dose and then the passage by forming, with required flux, dermal delivery permeable membrane thing to small part.For this reason, the subcutaneous fluid that passage extracted by at least one formation can cause dissolving and/or suspend be positioned over intramatrical permeable membrane thing to small part process, and then can spread back intraindividual feasible diffusion admittance for the permeable membrane thing provides the passage percutaneous by at least one formation in the skin.In case the permeable membrane thing is by the viable skin layer of dermal delivery to individuality, described permeable membrane thing can be that the local activated system that maybe can be recycled absorbs also systematicness distribution.For example, on the one hand, described permeable membrane thing can be absorbed by lymphsystem.
Based on the passive chemodiffusional driving force, also consider that other penetrating reinforcing agent can unite use with permeable membrane thing delivery matrices of the present invention except that as herein described.For example, and it is also unrestricted, delivery matrices of the present invention can use with the technical tie-up of active force reinforcing agent, and described active force reinforcing agent technology is the local deformation of application of sonic energy, machinery suction, pressurization or tissue for example, comprising phonophoresis, iontophoresis or electroporation.
In addition, also can apply extra electric power, to improve the percutaneous permeable membrane thing flux of permeable membrane thing by the passage of at least one formation in the individual's skin to the permeable membrane thing.Electrodynamic use for therapeutic dose such as protein, peptide and even the bigger macromole reagent of the gene dermal delivery that passes the skin of micropunch be useful especially.In addition, in other respects, and compare, can use to have still less and/or these delivery modality initiatively of littler passage by the common needed passage of isoflux mutually only for the system of passive diffusion.Thereby on the one hand, initiatively electrodynamic use can reduce the skin volume that will melt, makes described system littler to the invasive of user.
For this reason, on the one hand, can be configured to provide electro-osmotic pumps (EOP) assembling according to permeable membrane thing delivery matrices of the present invention.According to this respect, and describe as Fig. 5, the delivery matrices 20 (d) with micropunch of end face and opposed bottom surface also can comprise and is in the assembling of one or more first electrodes 60 of the electric connection of described end face and is in assembling with one or more second electrodes 70 of the electric connection of described bottom surface.Can provide described electrode assembling by the electrode placement technique of any routine well known by persons skilled in the art, for example spraying plating (sputtering), electro-deposition or electroless deposition.Then, by the assembling of described first and second electrodes is placed with voltage source or current source (V) optionally or controlled electric connection form complete loop.To near the stable permeable membrane thing stack that applies the opening of substrate that correct polar electric field can cause micropunch of the intramatrical permeable membrane thing of micropunch, thereby the dermal delivery that provides diffusion gradient to drive is gone into intraindividual relative reinforcement.
Still on the other hand, also can comprise third electrode or counter electrode according to electro-osmotic pumps assembling of the present invention, electric connection with individual's skin is placed and be adapted to itself and delivery matrices at a distance.The merging of third electrode or counter electrode makes electrodynamic application become possibility, and described electric power can strengthen the permeable membrane thing and move laterally to the focus consistent with at least one passage that forms from the bottom surface of the delivery matrices of micropunch in individual's skin.As what should recognize, this aspect of the present invention can provide extra percutaneous flux efficient, because it is almost nil to pass the flux of skin complete part, described skin complete partly has unbroken horny layer and does not have the passage of the formation of leading to the skin activity layer.
In the use, three electrodes assembling as indicated above can circulate according to the selectivity on-off of the different electrode assemblings in the electro-osmotic pumps assembling and operate.For example, in the circulation of first electro-osmotic pumps, can activate electro-osmotic pumps (EOP) by between the assembling of first and second electrodes, forming the loop, to produce the bioactivator of relative high concentration near the microporosity opening in the delivery matrices bottom surface.In the circulation of second electrotransport, can make in the assembling of the first and second EOP electrodes one or two charged, make its have use with the particular bioactive agent for the treatment of dermal delivery on the identical polarity of net charge.Then, can place at a distance with delivery matrices and be in being communicated with of skin surface in the third electrode assembling can be used as counter electrode and operate.In this electrotransport pattern, the electric repulsive force that produces on the bioactivator can drive bioactivator effectively and enter in the individual micropore.
Certainly, be to be understood that this electrotransport pattern (ETM) and electro-osmotic pumps pattern (EOP) can on-off mode be regulated, perhaps with close and maximum intensity between any level regulate.Remain in certain exemplary limit by amount and persistent period ETM, for example 10ms opens with 50ms and closes, the average current that passes the individual's skin tissue that flows in ETM can be maintained at enough low level, so that any variation of local pH all can be in the shut-in time of ETM, by the normal miniflow effect in the skin histology and the ionic diffusion naturally when not having electric field be neutralized.Should recognize that as those skilled in the art this can act on the uniform concentration of setting up all stream materials, thereby make pH turn back to its normal physiological status.Equally, this adjusting of the opening time of ETM to shut-in time also can be eliminated because the destructive stimulation of the normal pH of skin histology.
Be to be understood that EOP pattern or circulation and ETM pattern or concrete working cycle of circulation can be depending on the concrete permeable membrane thing for the treatment of dermal delivery and be applied to EOP and the levels of current of ETM.Rest on the rough calculation in a certain preset range although can guarantee the pH of active mass, in practice, can determine these working cycle by simply little pH pick off being placed the paster below to test with the effect in monitoring different operating cycle.Of the present invention other are characterized as integrates with paster with the pH sensing element, and the output of using described pH sensing element generation is as the feedback signal for system controller, thereby having realized guaranteeing remains on close loop control circuit in the scope of programming with pH, and need not to consider the variation between the individuality and individuality, other power that environmental factors maybe may influence local environment among the local skin physiology.
With reference to Fig. 6, described also to comprise the example patch assembling of three electrode osmotic pumps assembling among the figure.As shown in the figure, this exemplary means comprises the transdermal patch assembling, and this assembling contains the delivery matrices just like micropunch as herein described before.Described delivery matrices made up and be arranged to have end face and opposed bottom surface.Backing supporting layer with inside facing surfaces is connected in the end face of delivery matrices at least in part.The storage storehouse of sending of micropunch comprises end face and opposed bottom surface.First electrode assembling 60 is placed in the electric connection with described end face, and second electrode assembling 70 is placed in the electric connection with described bottom surface.The electric connection with individual's skin is placed and be adapted to be placed in to third electrode or counter electrode 80 and delivery matrices at a distance.Then, place and the selectivity of voltage or current source (not shown) or controlled electric connection by at least two, can produce complete loops between any at least two in first, second and third electrode with first, in the mat woven of fine bamboo strips two and the third electrode assembling.
Embodiment
Setting forth following examples is the abundant the disclosure and description how claimed device of this paper, system and method to be made, move and estimated in order to provide to those skilled in the art.These embodiment are intended to only the present invention be carried out exemplary explanation and are not intended to limit the inventor think its scope of invention.Unless point out in addition, umber is parts by weight, and temperature is ℃ or is that ambient temperature, pressure are atmospheric pressure or near atmospheric pressure.
Hydromorphone
Fig. 7 has reported that permeable membrane thing delivery patch thickness is to the vitro drug release effect of kinetics for various permeable membrane thing delivery patch of the present invention.Four kinds of permeable membrane thing delivery patch produced according to the present invention.In four kinds of substrate each contains vinyl-vinyl acetate copolymer (EVA).Be positioned over the intramatrical permeable membrane thing of EVA preparation contain as bioactivator dihydromorphinone hydrochloride (HM) and as the mannitol and the propylene glycol (PG) of filler component, and area is about 1.44cm 2First paster has the thickness of about 1.00mm and contains the 67mg hydromorphone of having an appointment.Second paster has the thickness of about 0.50mm and contains the 25mg dihydromorphinone hydrochloride of having an appointment.The 3rd paster has the thickness of about 0.44mm and contains the 22mg hydromorphone of having an appointment.The 4th paster has the thickness of about 0.22mm and contains the 11mg dihydromorphinone hydrochloride of having an appointment.
Be used for about 24 hours administration phase with using each testing in vitro in described four kinds of pasters to make up.Use the conventional analysis means, reported that by the curve of describing among Fig. 7 the accumulation dihydromorphinone hydrochloride that continues 24 hours administration phases in described four kinds of permeable membrane thing delivery patch each discharges and the relative percentage of dihydromorphinone hydrochloride release.
Fig. 8 reported on the abdomen part of four different no hair rat individualities, test, for average pharmacokinetics curve (PK curve) according to exemplary permeable membrane thing delivery apparatus of the present invention.This permeable membrane thing paster is to have the thickness of about 1.4mm and contain the film of the vinyl-vinyl acetate copolymer of 50 weight % as host material, and described vinyl-vinyl acetate copolymer has about 40% vinyl acetate component.This permeable membrane compositions contains the mannitol (with respect to the gross weight of permeable membrane thing paster) as 25 weight % of the dihydromorphinone hydrochloride of 25 weight % of bioactivator (with respect to the total weight percent of permeable membrane thing paster) and the extra filler component of conduct.Reported among Fig. 8 according to the average serum hydromorphone concentration in the no hair rat of the functions of 24 hours administration phases.
The citric acid fentanyl
Fig. 9 has reported the average citric acid fentanyl serum levels PK curve for the permeable membrane thing delivery patch of the present invention that comprises variable concentrations citric acid fentanyl.Particularly, shown according to the comparison of the average citric acid fentanyl serum levels PK curve of the delivery patch of 10% citric acid fentanyl of hereinafter similar process preparation.
Comprise exemplary permeable membrane thing delivery patch as 10% citric acid fentanyl of bioactivator Preparation
For preparing described paster, mannitol sieves with 200 eye mesh screens before use.Then, can be by will about 3000mg citric acid fentanyl and about 18450mg mannitol is packed in the bottle and allow the mixture blending to prepare described paster at least in 6 hours.The ethane-acetic acid ethyenyl ester of 40% vinyl acetate component of can being had an appointment containing of about 8550mg adds the mixture of the blending of citric acid fentanyl and mannitol.Can be with the material continuous stirring of packing into and in the vessel in heating of the controlled temperature temperature in about 80-120 ℃ scope.After mixture reaches dough shape denseness, this mixture can be transferred to backing film, for example can from
Figure BPA00001260572300491
The Scotchpak backing that obtains.
In case be positioned on the back lining materials, described dough material can be compressed in backing layer and anti-release liner layer (1521 single face polyethylene films for example, also can from Obtain) between, so that the paster with desired thickness to be provided.After the paster material cooling, can cut the film that obtains and for example be about 1cm to provide to have 2The paster of surface area.Paster according to the aforementioned process preparation can comprise the concentration of the bioactivator of the about 3.8mg citric acid of for example every paster fentanyl.Before example patch being applied to the test individuality, should remove anti-releasing layer earlier to expose the bottom surface of substrate.
Fig. 9 shows, in one aspect of the invention, can send the citric acid fentanyl by the micropore in the skin, and can control steady-state level by the fentanyl content of delivery patch.
Fentanyl is followed the trail of
For the fentanyl follow up study, once more the abdominal part that does not have the hair rat is carried out micropunch, use purpose film or solution then.Remove paster (film or solution) in the predetermined stipulated time (promptly using back 12 hours), and cover medicine-feeding part to have filled the follow-up of the saturated citric acid fentanyl of about 200 μ L solution or to have followed the trail of liquid storage storehouse paster.Then, take out blood sample (usually after the sheet of exchangining cards containing all personal details and become sworn brothers after 6-10 hour or the micropunch 18-22 hour) from the tail vein that does not have the hair rat.Separation of serum is used for the fentanyl analysis from blood sample.
Figure 10 illustrates the data that this fentanyl follow up study produces.Used a kind of preparation (listing) 12 hours afterwards, and covered this position and begin blood sampling with saturated citric acid fentanyl solution at the x axle.The average serum fentanyl level that reached in 6-10 hour behind the fentanyl solution is used in the representative of y axle.The representative of contrast post is applied to saturated citric acid fentanyl solution the level that obtained in 6-10 hour behind the skin of micropunch recently.Can obviously find out from data, cover the position 12 hours of micropunch recently, prevent sending of fentanyl by using the film of making alone by EVA.If use the film made by EVA/ mannitol or cover described position, obtain identical near the result with saturated mannitol solution.On the other hand, if at first cover described position, then observe about 60% and 85% level respectively available from the fentanyl level of contrast with the film that contains fentanyl or hydromorphone.
Insulin
Figure 11 has reported that explanation adds water-soluble polymer polyvinyl alcohol (PVA) in the chart that comprises as the effect of the insulin preparation of the Tris of permeability reinforcing agent.Adding polymer provides the insulin of prolongation to send curve by control medicine and/or permeability reinforcing agent from the release of film.Matrix scaffold is made up of ethane-acetic acid ethyenyl ester (EVA).
Figure 12 has reported that explanation adds insoluble polymer ethyl cellulose (EC) in the chart that comprises as the effect of the insulin preparation of the Tris of permeability reinforcing agent.Adding polymer provides the insulin of prolongation to send curve by control medicine and/or permeability reinforcing agent from the release of film.Matrix scaffold is made up of ethane-acetic acid ethyenyl ester (EVA).
Exenatide
Figure 13 has reported and has illustrated that different permeability reinforcing agents are not to there being the chart of the influence that Exenatide is sent in the hair rat.Abdominal part animal carries out micropunch and use the paster that contains 200 μ L Exenatide solution (10.5mg/mL) and purpose reagent (3%w/v) on this position.Used fresh solution again in per 4 hours on this position and in 24 hours blood sampling be used for the Exenatide level.Disodium citrate provided roughly stable level during 24 hours when, the use of succinic acid or maleic acid provided the level that increases.
Figure 14 has reported the chart of explanation effect of succinic acid (SA) and ethyl cellulose (EC) in the preparation that the Exenatide that is designed to realize to surpass 24 hours prolongation is sent.With respect to the preparation that comprises 57% disodium citrate (DiNaCitrate), 30% succinic acid preparation provides higher Cmax and area under curve (AUC).Matrix scaffold is made up of ethane-acetic acid ethyenyl ester (EVA).
Figure 15 has reported the chart of the influence that explanation polymer and/or permeability reinforcing agent discharge external Exenatide.Can change permeability reinforcing agent body (identity) or component to change the solubility curve of film.For example, the film that contains 30% ethyl cellulose discharges Exenatide than the film that contains 45% ethyl cellulose with faster rate.
Figure 16 has reported that explanation permeability enhancer component is to the chart of Exenatide from the influence of the release in vitro of the Exenatide film that comprises ethane-acetic acid ethyenyl ester (EVA) and purpose permeability reinforcing agent.Increase disodium citrate percentage ratio and have the effect of slowing down the speed that Exenatide discharges from film.
Hole permeability reinforcing agent
Figure 17 has reported the influence of permeability reinforcing agent body to the maintenance of hole permeability.Prepare polymeric film with EVA and about 70% the permeability reinforcing agent listed.Do not carry out micropunch and place the position of micropunch to continue 12 hours described film there being the hair rat, then, replace described polymeric film and monitoring of blood fentanyl level with the liquid storage storehouse paster that contains citric acid fentanyl solution.During without any the permeability reinforcing agent (film that only contains 100%EVA), use the fentanyl level that reaches after the fentanyl solution less than 5ng/mL, yet, as shown in the figure, comprise the permeability reinforcing agent and produce significantly higher fentanyl level.Right axle be given in remove last paster after described position skin pH as a reference.Should be noted that this only is the limiting examples of permeability reinforcing agent body to the screening technique of the influence of the maintenance of hole permeability.Can use and test additive method and other permeability reinforcing agents.

Claims (108)

1. be used for sending by the biomembrane of individuality the paster of permeable membrane thing, it comprises:
A) substrate;
B) at least a hydrophilic permeable membrane thing that is positioned in the described substrate, wherein the described hydrophilic permeable membrane thing to small part can be dissolved in from the biological moisture that described individuality obtains; With
C) at least a permeability reinforcing agent that is positioned in the described substrate.
2. paster as claimed in claim 1, wherein said hydrophilic permeable membrane thing is a bioactivator.
3. paster as claimed in claim 2, wherein said bioactivator is a protein drug.
4. paster as claimed in claim 3, wherein said protein drug is an Exenatide.
5. paster as claimed in claim 3, wherein said protein drug is an insulin.
6. paster as claimed in claim 2, wherein said bioactivator is a hydromorphone.
7. paster as claimed in claim 2, wherein said bioactivator are the citric acid fentanyls.
8. paster as claimed in claim 1, wherein said permeability reinforcing agent is the pH controlling agent.
9. paster as claimed in claim 8, wherein said pH controlling agent is selected from succinic acid, disodium citrate, trisodium citrate and Tris.
10. paster as claimed in claim 8, wherein said pH controlling agent is a succinic acid.
11. paster as claimed in claim 8, wherein said pH controlling agent is a disodium citrate.
12. paster as claimed in claim 1, wherein said substrate comprises at least a polymer.
13. paster as claimed in claim 12, wherein said polymer is an insoluble polymer.
14. paster as claimed in claim 12, wherein said polymer is a water-soluble polymer.
15. paster as claimed in claim 12, wherein said substrate comprises two or more polymer.
16. paster as claimed in claim 15, wherein said substrate comprise at least a insoluble polymer and at least a water-soluble polymer.
17. paster as claimed in claim 13, wherein said insoluble polymer is selected from ethane-acetic acid ethyenyl ester and ethyl cellulose.
18. paster as claimed in claim 14, wherein said water-soluble polymer is selected from Polyethylene Glycol, polyvinyl alcohol and polyvinylpyrrolidone.
19. paster as claimed in claim 1 also comprises the dissolubility controlling agent.
20. paster as claimed in claim 19, wherein said dissolubility controlling agent is selected from sodium chloride and ammonium sulfate.
21. paster as claimed in claim 1, extremely about 24 hours administration phase was delivered to individuality from about 5 minutes wherein described hydrophilic permeable membrane thing to be continued scope.
22. paster as claimed in claim 19, extremely about 24 hours administration phase was delivered to individuality from about 5 minutes wherein described hydrophilic permeable membrane thing to be continued scope.
23. paster as claimed in claim 21, wherein said administration phase scope was from about 12 to about 24 hours.
24. paster as claimed in claim 22, wherein said administration phase scope was from about 12 to about 24 hours.
25. paster as claimed in claim 21, wherein said administration phase scope was from about 6 hours to about 12 hours.
26. paster as claimed in claim 22, wherein said administration phase scope was from about 6 hours to about 12 hours.
27. paster as claimed in claim 21, wherein said administration phase scope was from about 1 hour to about 6 hours.
28. paster as claimed in claim 22, wherein said administration phase scope was from about 1 hour to about 6 hours.
29. paster as claimed in claim 21, wherein said administration phase scope was from about 5 minutes to about 1 hour.
30. paster as claimed in claim 22, wherein said administration phase scope was from about 5 minutes to about 1 hour.
31. be used for sending by individual biomembrane the system of permeable membrane thing, it comprises:
A) perforator; With
B) paster, wherein said paster comprises:
I) substrate;
The ii) at least a hydrophilic permeable membrane thing that is positioned in the described substrate wherein can be dissolved in by the micropore that formed by described perforator from the biological moisture that described individuality obtains to the described hydrophilic permeable membrane thing of small part; With
The iii) at least a permeability reinforcing agent that is positioned in the described substrate.
32. system as claimed in claim 31, wherein said perforator is selected from hot piercing device, machine drilling device, laser beam perforation device and hydraulic perforating gun.
33. system as claimed in claim 31, wherein said perforator is a heat-conduction component, and described heat-conduction component is in and contacts with the physics of described biomembranous essence so that enough energy are delivered to described biomembrane, thus the described biomembrane of heating ablation.
34. system as claimed in claim 31, wherein said perforator is a thin film organizational interface device.
35. system as claimed in claim 31, wherein said hydrophilic permeable membrane thing is a bioactivator.
36. system as claimed in claim 35, wherein said bioactivator is a protein drug.
37. system as claimed in claim 36, wherein said protein drug is an Exenatide.
38. system as claimed in claim 36, wherein said protein drug is an insulin.
39. system as claimed in claim 35, wherein said bioactivator is a hydromorphone.
40. system as claimed in claim 35, wherein said bioactivator is the citric acid fentanyl.
41. system as claimed in claim 31, wherein said permeability reinforcing agent is the pH controlling agent.
42. system as claimed in claim 41, wherein said pH controlling agent is selected from succinic acid, disodium citrate, trisodium citrate and Tris.
43. system as claimed in claim 41, wherein said pH controlling agent is a succinic acid.
44. system as claimed in claim 41, wherein said pH controlling agent is a disodium citrate.
45. system as claimed in claim 31, wherein said substrate comprises at least a polymer.
46. system as claimed in claim 45, wherein said polymer is an insoluble polymer.
47. system as claimed in claim 45, wherein said polymer is a water-soluble polymer.
48. system as claimed in claim 45, wherein said substrate comprises two or more polymer.
49. system as claimed in claim 48, wherein said substrate comprise at least a insoluble polymer and at least a water-soluble polymer.
50. system as claimed in claim 46, wherein said insoluble polymer is selected from ethane-acetic acid ethyenyl ester and ethyl cellulose.
51. system as claimed in claim 47, wherein said water-soluble polymer is selected from Polyethylene Glycol, polyvinyl alcohol and polyvinylpyrrolidone.
52. system as claimed in claim 31 also comprises the dissolubility controlling agent.
53. system as claimed in claim 52, wherein said dissolubility controlling agent is selected from sodium chloride and ammonium sulfate.
54. system as claimed in claim 31, extremely about 24 hours administration phase was delivered to individuality from about 5 minutes wherein described hydrophilic permeable membrane thing to be continued scope.
55. system as claimed in claim 52, extremely about 24 hours administration phase was delivered to individuality from about 5 minutes wherein described hydrophilic permeable membrane thing to be continued scope.
56. system as claimed in claim 54, wherein said administration phase scope was from about 12 to about 24 hours.
57. system as claimed in claim 55, wherein said administration phase scope was from about 12 to about 24 hours.
58. system as claimed in claim 54, wherein said administration phase scope was from about 6 hours to about 12 hours.
59. system as claimed in claim 55, wherein said administration phase scope was from about 6 hours to about 12 hours.
60. system as claimed in claim 54, wherein said administration phase scope was from about 1 hour to about 6 hours.
61. system as claimed in claim 55, wherein said administration phase scope was from about 1 hour to about 6 hours.
62. system as claimed in claim 54, wherein said administration phase scope was from about 5 minutes to about 1 hour.
63. system as claimed in claim 55, wherein said administration phase scope was from about 5 minutes to about 1 hour.
64. by the method that individual biomembrane is sent the permeable membrane thing, it comprises:
A) in described biomembrane, form one or more micropores; And
B) paster is in the physics of described one or more micropores and contacts, wherein said paster comprises:
I) substrate;
The ii) at least a hydrophilic permeable membrane thing that is positioned in the described substrate, wherein the described hydrophilic permeable membrane thing to small part can be dissolved in by described one or more micropores from the biological moisture that described individuality obtains; With
The iii) at least a permeability reinforcing agent that is positioned in the described substrate.
65. as the described method of claim 64, wherein use is selected from following device and forms described one or more micropore: hot piercing device, machine drilling device, laser beam perforation device and hydraulic perforating gun.
66. as the described method of claim 64, wherein use heat-conduction component to form described one or more micropore, described heat-conduction component is in and contacts with the physics of described biomembranous essence so that enough energy are delivered to described biomembrane, thus the described biomembrane of heating ablation.
67., wherein use thin film organizational interface device to form described one or more micropore as the described method of claim 64.
68. as the described method of claim 64, wherein said hydrophilic permeable membrane thing is a bioactivator.
69. as the described method of claim 68, wherein said bioactivator is a protein drug.
70. as the described method of claim 69, wherein said protein drug is an Exenatide.
71. as the described method of claim 69, wherein said protein drug is an insulin.
72. as the described method of claim 68, wherein said bioactivator is a hydromorphone.
73. as the described method of claim 68, wherein said bioactivator is the citric acid fentanyl.
74. as the described method of claim 64, wherein said permeability reinforcing agent is the pH controlling agent.
75. as the described method of claim 74, wherein said pH controlling agent is selected from succinic acid, disodium citrate, trisodium citrate and Tris.
76. as the described method of claim 74, wherein said pH controlling agent is a succinic acid.
77. as the described method of claim 74, wherein said pH controlling agent is a disodium citrate.
78. as the described method of claim 64, wherein said substrate comprises at least a polymer.
79. as the described method of claim 78, wherein said polymer is an insoluble polymer.
80. as the described method of claim 78, wherein said polymer is a water-soluble polymer.
81. as the described method of claim 78, wherein said substrate comprises two or more polymer.
82. as the described method of claim 81, wherein said substrate comprises at least a insoluble polymer and at least a water-soluble polymer.
83. as the described method of claim 79, wherein said insoluble polymer is selected from ethane-acetic acid ethyenyl ester and ethyl cellulose.
84. as the described method of claim 80, wherein said water-soluble polymer is selected from Polyethylene Glycol, polyvinyl alcohol and polyvinylpyrrolidone.
85., also comprise the dissolubility controlling agent as the described method of claim 64.
86. as the described method of claim 85, wherein said dissolubility controlling agent is selected from sodium chloride and ammonium sulfate.
87. as the described method of claim 64, extremely about 24 hours administration phase was delivered to individuality from about 5 minutes wherein described hydrophilic permeable membrane thing to be continued scope.
88. as the described method of claim 85, extremely about 24 hours administration phase was delivered to individuality from about 5 minutes wherein described hydrophilic permeable membrane thing to be continued scope.
89. as the described method of claim 87, wherein said administration phase scope was from about 12 to about 24 hours.
90. as the described method of claim 88, wherein said administration phase scope was from about 12 to about 24 hours.
91. as the described method of claim 87, wherein said administration phase scope was from about 6 hours to about 12 hours.
92. as the described method of claim 88, wherein said administration phase scope was from about 6 hours to about 12 hours.
93. as the described method of claim 87, wherein said administration phase scope was from about 1 hour to about 6 hours.
94. as the described method of claim 88, wherein said administration phase scope was from about 1 hour to about 6 hours.
95. as the described method of claim 87, wherein said administration phase scope was from about 5 minutes to about 1 hour.
96. as the described method of claim 88, wherein said administration phase scope was from about 5 minutes to about 1 hour.
97. paster as claimed in claim 1 wherein is delivered to individuality with lasting about 3 days administration phase of described hydrophilic permeable membrane thing.
98. paster as claimed in claim 1 wherein is delivered to individuality with lasting about 7 days administration phase of described hydrophilic permeable membrane thing.
99. paster as claimed in claim 19 wherein is delivered to individuality with lasting about 3 days administration phase of described hydrophilic permeable membrane thing.
100. paster as claimed in claim 19 wherein is delivered to individuality with lasting about 7 days administration phase of described hydrophilic permeable membrane thing.
101. system as claimed in claim 31 wherein is delivered to individuality with lasting about 3 days administration phase of described hydrophilic permeable membrane thing.
102. system as claimed in claim 31 wherein is delivered to individuality with lasting about 7 days administration phase of described hydrophilic permeable membrane thing.
103. system as claimed in claim 52 wherein is delivered to individuality with lasting about 3 days administration phase of described hydrophilic permeable membrane thing.
104. system as claimed in claim 52 wherein is delivered to individuality with lasting about 7 days administration phase of described hydrophilic permeable membrane thing.
105., wherein lasting about 3 days administration phase of described hydrophilic permeable membrane thing is delivered to individuality as the described method of claim 64.
106., wherein lasting about 7 days administration phase of described hydrophilic permeable membrane thing is delivered to individuality as the described method of claim 64.
107., wherein lasting about 3 days administration phase of described hydrophilic permeable membrane thing is delivered to individuality as the described method of claim 85.
108., wherein lasting about 7 days administration phase of described hydrophilic permeable membrane thing is delivered to individuality as the described method of claim 85.
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